ID: 22766032
Title: Association of UBQLN1 mutation with Brown-Vialetto-Van Laere syndrome but not typical ALS.
Abstract: Genetic variants in UBQLN1 gene have been linked to neurodegeneration and mutations in UBQLN2 have recently been identified as a rare cause of amyotrophic lateral sclerosis (ALS). To test if genetic variants in UBQLN1 are involved in ALS. 102 and 94 unrelated patients with familial and sporadic forms of ALS were screened for UBQLN1 gene mutations. Single nucleotide variants were further screened in a larger set of sporadic ALS (SALS) patients and unrelated control subjects using high-throughput Taqman genotyping; variants were further assessed for novelty using the 1000Genomes and NHLBI databases. In vitro studies tested the effect of UBQLN1 variants on the ubiquitin-proteasome system (UPS). Only two UBQLN1 coding variants were detected in the familial and sporadic ALS DNA set; one, the missense mutation p.E54D, was identified in a single patient with atypical motor neuron disease consistent with Brown-Vialetto-Van Laere syndrome (BVVLS), for whom c20orf54 mutations had been excluded. Functional studies revealed that UBQLN1E54D protein forms cytosolic aggregates that contain mislocalized TDP-43 and impairs degradation of ubiquitinated proteins through the proteasome. Genetic variants in UBQLN1 are not commonly associated with ALS. A novel UBQLN1 mutation (E45D) detected in a patient with BVVLS altered nuclear TDP-43 localization in vitro, suggesting that UPS dysfunction may also underlie the pathogenesis of this condition.

ID: 35286755
Title: DNAJB2-related Charcot-Marie-Tooth disease type 2: Pathomechanism insights and phenotypic spectrum widening.
Abstract: Mutations in DNAJB2 are associated with autosomal recessive hereditary motor neuropathies/ Charcot-Marie-Tooth disease type 2 (CMT2). We describe an Italian family with CMT2 due to a homozygous DNAJB2 mutation and provide insight into the pathomechanisms. Patients with DNAJB2 mutations were characterized clinically, electrophysiologically and by means of skin biopsy. mRNA and protein levels were studied in lymphoblastoid cells (LCLs) from patients and controls. Three affected siblings were found to carry a homozygous DNAJB2 null mutation segregating with the disease. The disease manifested in the second to third decade of life. Clinical examination showed severe weakness of the thigh muscles and complete loss of movement in the foot and leg muscles. Sensation was reduced in the lower limbs. All patients had severe hearing loss and the proband also had Parkinson's disease (PD). Nerve conduction studies showed an axonal motor and sensory length-dependent polyneuropathy. DNAJB2 expression studies revealed reduced mRNA levels and the absence of the protein in the homozygous subject in both LCLs and skin biopsy. Interestingly, we detected phospho-alpha-synuclein deposits in the proband, as already seen in PD patients, and demonstrated TDP-43 accumulation in patients' skin. Our results broaden the clinical spectrum of DNAJB2-related neuropathies and provide evidence that DNAJB2 mutations should be taken into account as another causative gene of CMT2 with hearing loss and parkinsonism. The mutation likely acts through a loss-of-function mechanism, leading to toxic protein aggregation such as TDP-43. The associated parkinsonism resembles the classic PD form with the addition of abnormal accumulation of phospho-alpha-synuclein.

ID: 37532939
Title: TDP-43 forms amyloid filaments with a distinct fold in type A FTLD-TDP.
Abstract: The abnormal assembly of TAR DNA-binding protein 43 (TDP-43) in neuronal and glial cells characterizes nearly all cases of amyotrophic lateral sclerosis (ALS) and around half of cases of frontotemporal lobar degeneration (FTLD)1,2. A causal role for TDP-43 assembly in neurodegeneration is evidenced by dominantly inherited missense mutations in TARDBP, the gene encoding TDP-43, that promote assembly and give rise to ALS and FTLD3-7. At least four types (A-D) of FTLD with TDP-43 pathology (FTLD-TDP) are defined by distinct brain distributions of assembled TDP-43 and are associated with different clinical presentations of frontotemporal dementia8. We previously showed, using cryo-electron microscopy, that TDP-43 assembles into amyloid filaments in ALS and type B FTLD-TDP9. However, the structures of assembled TDP-43 in FTLD without ALS remained unknown. Here we report the cryo-electron microscopy structures of assembled TDP-43 from the brains of three individuals with the most common type of FTLD-TDP, type A. TDP-43 formed amyloid filaments with a new fold that was the same across individuals, indicating that this fold may characterize type A FTLD-TDP. The fold resembles a chevron badge and is unlike the double-spiral-shaped fold of ALS and type B FTLD-TDP, establishing that distinct filament folds of TDP-43 characterize different neurodegenerative conditions. The structures, in combination with mass spectrometry, led to the identification of two new post-translational modifications of assembled TDP-43, citrullination and monomethylation of R293, and indicate that they may facilitate filament formation and observed structural variation in individual filaments. The structures of TDP-43 filaments from type A FTLD-TDP will guide mechanistic studies of TDP-43 assembly, as well as the development of diagnostic and therapeutic compounds for TDP-43 proteinopathies.

ID: 38807021
Title: Advances in Exosome-Based Therapies for the Repair of Peripheral Nerve Injuries.
Abstract: Peripheral nerve injuries (PNIs) are the term used to describe injuries that occur to the nerve fibers of the peripheral nervous system (PNS). Such injuries may be caused by trauma, infection, or aberrant immunological response. Although the peripheral nervous system has a limited capacity for self-repair, in cases of severe damage, this process is either interrupted entirely or is only partially completed. The evaluation of variables that promote the repair of peripheral nerves has consistently been a focal point. Exosomes are a subtype of extracellular vesicles that originate from cellular sources and possess abundant proteins, lipids, and nucleic acids, play a critical role in facilitating intercellular communication. Due to their modifiable composition, they possess exceptional capabilities as carriers for therapeutic compounds, including but not limited to mRNAs or microRNAs. Exosome-based therapies have gained significant attention in the treatment of several nervous system diseases due to their advantageous properties, such as low toxicity, high stability, and limited immune system activation. The objective of this review article is to provide an overview of exosome-based treatments that have been developed in recent years for a range of PNIs, including nerve trauma, diabetic neuropathy, amyotrophic lateral sclerosis (ALS), glaucoma, and Guillain-Barre syndrome (GBS). It was concluded that exosomes could provide favorable results in the improvement of peripheral PNIs by facilitating the transfer of regenerative factors. The development of bioengineered exosome therapy for PNIs should be given more attention to enhance the efficacy of exosome treatment for PNIs.

ID: 39072727
Title: Quantitative proteomics unveils known and previously unrecognized alterations in neuropathic nerves.
Abstract: Charcot-Marie-Tooth disease type 1E (CMT1E) is an inherited autosomal dominant peripheral neuropathy caused by mutations in the peripheral myelin protein 22 (PMP22) gene. The identical leucine-to-proline (L16P) amino acid substitution in PMP22 is carried by the Trembler J (TrJ) mouse and is found in CMT1E patients presenting with early-onset disease. Peripheral nerves of patients diagnosed with CMT1E display a complex and varied histopathology, including Schwann cell hyperproliferation, abnormally thin myelin, axonal degeneration, and subaxonal morphological changes. Here, we have taken an unbiased data-independent analysis (DIA) mass spectrometry (MS) approach to quantify proteins from nerves of 3-week-old, age and genetic strain-matched wild-type (Wt) and heterozygous TrJ mice. Nerve proteins were dissolved in lysis buffer and digested into peptide fragments, and protein groups were quantified by liquid chromatography-mass spectrometry (LC-MS). A linear model determined statistically significant differences between the study groups, and proteins with an adjusted p-value of less than 0.05 were deemed significant. This untargeted proteomics approach identified 3759 quality-controlled protein groups, of which 884 demonstrated differential expression between the two genotypes. Gene ontology (GO) terms related to myelin and myelin maintenance confirm published data while revealing a previously undetected prominent decrease in peripheral myelin protein 2. The dataset corroborates the described pathophysiology of TrJ nerves, including elevated activity in the proteasome-lysosomal pathways, alterations in protein trafficking, and an increase in three macrophage-associated proteins. Previously unrecognized perturbations in RNA processing pathways and GO terms were also discovered. Proteomic abnormalities that overlap with other human neurological disorders besides CMT include Lafora Disease and Amyotrophic Lateral Sclerosis. Overall, this study confirms and extends current knowledge on the cellular pathophysiology in TrJ neuropathic nerves and provides novel insights for future examinations. Recognition of shared pathomechanisms across discrete neurological disorders offers opportunities for innovative disease-modifying therapeutics that could be effective for distinct neuropathies.

ID: 39149866
Title: Schwann cell JUN expression worsens motor performance in an amyotrophic lateral sclerosis mouse model.
Abstract: Amyotrophic lateral sclerosis is a devastating neurodegenerative disease characterized by motor neuron death and distal axonopathy. Despite its clinical severity and profound impact in the patients and their families, many questions about its pathogenesis remain still unclear, including the role of Schwann cells and axon-glial signaling in disease progression. Upon axonal injury, upregulation of JUN transcription factor promotes Schwann cell reprogramming into a repair phenotype that favors axon regrowth and neuronal survival. To study the potential role of repair Schwann cells on motoneuron survival in amyotrophic lateral sclerosis, we generated a mouse line that over-expresses JUN in the Schwann cells of the SOD1G93A mutant, a mouse model of this disease. Then, we explored disease progression by evaluating survival, motor performance and histology of peripheral nerves and spinal cord of these mice. We found that Schwann cell JUN overexpression does not prevent axon degeneration neither motor neuron death in the SOD1G93A mice. Instead, it induces a partial demyelination of medium and large size axons, worsening motor performance and resulting in more aggressive disease phenotype.

ID: 39237477
Title: Gap detection ability declines with central auditory neurodegeneration following age-related cochlear synaptopathy.
Abstract: Age-related hearing impairment (ARHI) is commonly associated with decreased auditory temporal resolution caused by auditory neurodegeneration. Age-related deterioration in gap detection ability, resulting in poor temporal auditory processing, is often attributed to pathophysiological changes in both the peripheral and central auditory systems. This study aimed to investigate whether the gap detection ability declines in the early stages of ageing and to determine its usefulness in detecting peripheral and central auditory degeneration. The study used 1-month-old (1 M), 6-month-old (6 M) and 12-month-old (12 M) mice to examine changes in gap detection ability and associated auditory pathophysiology. Although hearing thresholds did not significantly differ between the groups, the amplitude of auditory brainstem response (ABR) wave I decreased significantly in an age-dependent manner, consistent with age-related cochlear synaptopathy. The relative ABR amplitude ratio of waves 2 and 5 to wave 1 was significantly increased in 12 M mice, indicating that the central auditory system had increased in relative neuroactivity. A significant increase in gap detection thresholds was observed in 12 M mice compared to 1 M mice. Although cochlear synaptopathy and central hyperactivity were positively correlated with gap detection thresholds, central hyperactivity strongly influenced gap detection ability. In the cochlear nucleus and auditory cortex, the inhibitory synaptic expression of GAD65 and the expression of parvalbumin were significantly decreased in 12 M mice, consistent with central hyperactivity. Evaluating gap detection performance may allow the identification of decreased auditory temporal resolution in the early stages of ARHI, which is strongly associated with auditory neurodegeneration.

ID: 39391989
Title: Hereditary spastic paraplegia with thin corpus callosum and SPG11 mutation: A neuropathological evaluation.
Abstract: Hereditary spastic paraplegia (HSP) with thin corpus callosum can be due to a variety of genetic causes, the most common of which are biallelic variants in SPG11 (HSP11). Only six cases of neuropathologic examination of HSP11 have been reported. Here we present neuropathological findings in another case of HSP11 with novel mutation (homozygous c.6439_6442del) and clinical features of three additional cases of HSP11. These four cases of HSP11 had similar disease courses with prominent lower extremity weakness and spasticity but varied cognitive symptoms and brain magnetic resonance imaging (MRI) findings. Neuropathological examination of one case included ex vivo MRI of the cerebrum, histologic and immunohistochemical evaluation, and Western blot for SPG11. The case was notable for a small cerebrum with decreased volume of cortex, white matter, and deep gray nuclei. The corpus callosum was thin, and the substantia nigra showed marked pallor. Microscopically, the cortex had normal lamination and mild loss of neurons with mild gliosis, the corpus callosum was thin with limited gliosis, and the substantia nigra had marked decrease in neurons and pigment, with minimal gliosis. In contrast, the basal ganglia, thalamus, and spinal cord (anterior horns, corticospinal, and spinocerebellar tracts) had prominent neuron loss and gliosis. Myelin-laden macrophages were found in multiple sites but were most common in the corpus callosum. No hyperphosphorylated tau or TDP-43 aggregates, Lewy bodies, or amyloid β plaques were found. Compared to control, SPG11 was absent in HSP11 brain and markers of autophagy were elevated by Western blot. Comparison with prior reports of HSP with thin corpus callosum and HSP11 demonstrates a disease with a broad range of structural changes of the brain, including features of abnormal development and degeneration.

ID: 39440303
Title: Dynactin-1 mediates rescue of impaired axonal transport due to reduced mitochondrial bioenergetics in amyotrophic lateral sclerosis motor neurons.
Abstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the motor system with complex determinants, including genetic and non-genetic factors. A key pathological signature of ALS is the cytoplasmic mislocalization and aggregation of TDP-43 in affected motor neurons, which is found in 97% of cases. Recent reports have shown that mitochondrial dysfunction plays a significant role in motor neuron degeneration in ALS, and TDP-43 modulates several mitochondrial transcripts. In this study, we used induced pluripotent stem cell-derived motor neurons from ALS patients with TDP-43 mutations and a transgenic TDP-43M337V mouse model to determine how TDP-43 mutations alter mitochondrial function and axonal transport. We detected significantly reduced mitochondrial respiration and ATP production in patient induced pluripotent stem cell-derived motor neurons, linked to an interaction between TDP-43M337V with ATPB and COX5A. A downstream reduction in speed of retrograde axonal transport in patient induced pluripotent stem cell-derived motor neurons was detected, which correlated with downregulation of the motor protein complex, DCTN1/dynein. Overexpression of DCTN1 in patient induced pluripotent stem cell-derived motor neurons significantly increased the percentage of retrograde travelling mitochondria and reduced the percentage of stationary mitochondria. This study shows that ALS induced pluripotent stem cell-derived motor neurons with mutations in TDP-43 have deficiencies in essential mitochondrial functions with downstream effects on retrograde axonal transport, which can be partially rescued by DCTN1 overexpression.

ID: 39603486
Title: Two cardinal features of ALS, reduced STMN2 and pathogenic TDP-43, synergize to accelerate motor decline in mice.
Abstract: Pathological TDP-43 loss from the nucleus and cytoplasmic aggregation occurs in almost all cases of ALS and half of frontotemporal dementia patients. Stathmin2 (Stmn2) is a key target of TDP-43 regulation and aberrantly spliced Stmn2 mRNA is found in patients with ALS, frontotemporal dementia, and Alzheimer's Disease. STMN2 participates in the axon injury response and its depletion in vivo partially replicates ALS-like symptoms including progressive motor deficits and distal NMJ denervation. The interaction between STMN2 loss and TDP-43 dysfunction has not been studied in mice because TDP-43 regulates human but not murine Stmn2 splicing. Therefore, we generated trans-heterozygous mice that lack one functional copy of Stmn2 and express one mutant TDP-43Q331K knock-in allele to investigate whether reduced STMN2 function exacerbates TDP-43-dependent pathology. Indeed, we observe synergy between these two alleles, resulting in an early onset, progressive motor deficit. Surprisingly, this behavioral defect is not accompanied by detectable neuropathology in the brain, spinal cord, peripheral nerves or at neuromuscular junctions (NMJs). However, the trans-heterozygous mice exhibit abnormal mitochondrial morphology in their distal axons and NMJs. As both STMN2 and TDP-43 affect mitochondrial dynamics, and neuronal mitochondrial dysfunction is a cardinal feature of many neurodegenerative diseases, this abnormality likely contributes to the observed motor deficit. These findings demonstrate that partial loss of STMN2 significantly exacerbates TDP-43-associated phenotypes, suggesting that STMN2 restoration could ameliorate TDP-43 related disease before the onset of degeneration.

ID: 39817908
Title: Opposing roles of p38α-mediated phosphorylation and PRMT1-mediated arginine methylation in driving TDP-43 proteinopathy.
Abstract: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder typically characterized by insoluble inclusions of hyperphosphorylated TDP-43. The mechanisms underlying toxic TDP-43 accumulation are not understood. Persistent activation of p38 mitogen-activated protein kinase (MAPK) is implicated in ALS. However, it is unclear how p38 MAPK affects TDP-43 proteinopathy. Here, we show that p38α MAPK inhibition reduces pathological TDP-43 phosphorylation, aggregation, cytoplasmic mislocalization, and neurotoxicity. Remarkably, p38α MAPK inhibition mitigates aberrant TDP-43 phenotypes in diverse ALS patient-derived motor neurons. p38α MAPK phosphorylates TDP-43 at pathological S409/S410 and S292, which reduces TDP-43 liquid-liquid phase separation (LLPS) but allows pathological TDP-43 aggregation. Moreover, we establish that PRMT1 methylates TDP-43 at R293. Importantly, S292 phosphorylation reduces R293 methylation, and R293 methylation reduces S409/S410 phosphorylation. Notably, R293 methylation permits TDP-43 LLPS and reduces pathological TDP-43 aggregation. Thus, strategies to reduce p38α-mediated TDP-43 phosphorylation and promote PRMT1-mediated R293 methylation could have therapeutic utility for ALS and related TDP-43 proteinopathies.

ID: 39932015
Title: Diffusion-Weighted Magnetic Resonance Imaging: A Diagnostic Tool for Auditory (Axonal) Neuropathy.
Abstract: Axonal neuropathies are disorders that impair neural transmission, leading to substantial sensory deficits. In the auditory system, axonal degeneration can disrupt auditory processing, causing significant hearing difficulties. Understanding the extent of axonal degeneration and its impact on auditory function is crucial for improving diagnosis and management. This study aims to quantify axonal degeneration in the VIIIth nerve using diffusion-weighted MRI and to correlate these findings with auditory function. Fifty-two children and adults participated. A total of, 27 with normal hearing, 7 with cochlear hearing loss and 18 with auditory neuropathy (AN). Hearing thresholds and dMRI data was collected for all participants and the VIIIth nerve was evaluated using the fixel-based analysis metric of Apparent Fibre Density (AFD). AFD was significantly lower in participants with AN compared to participants with normal hearing and cochlear hearing loss (p < 0.05). 9/18 participants with AN exhibited AFD values ≥ 2 standard deviations below the normal range. Additionally, AFD was strongly correlated with hearing thresholds in participants with no evidence of cochlear dysfunction (r = -0.776, p < 0.001), suggesting reduced auditory nerve fibre density is associated with impaired sound detection. dMRI-derived AFD is a sensitive marker for axonal degeneration in the VIIIth nerve. This study provides the first in vivo evidence linking VIIIth nerve microstructure with hearing thresholds, highlighting the potential of dMRI in diagnosing and monitoring AN. The findings suggest that dMRI could be a valuable tool in clinical settings for assessing auditory nerve health and guiding treatment strategies for individuals with AN.

ID: 40555518
Title: ALS Mutations Shift the Isoelectric Point of the KIF5A C Terminal Inducing Protein Aggregation and TDP-43 Mislocalization.
Abstract: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by death of lower and upper motor neurons. Although the mechanism behind the selective neuron loss is still unclear, several heterogeneous genes have been causally linked to ALS. KIF5A encodes for a neuronally enriched kinesin involved in protein transport, and mutations within this gene have been causally linked to different motor neuron diseases. The mutations identified in ALS patients are mostly predicted to alter its mRNA splicing, leading to a frameshift mutation and an aberrant 39-aa-long sequence in the C-terminal domain of KIF5A. Here we found that ALS-related KIF5A mutations induce the accumulation of the mutant form of the protein in human motoneurons, which are also characterized by the cytosolic mislocalization of TDP-43. This ALS hallmark was even exacerbated upon overexpression of the ALS-KIF5A protein in cells differentiated from healthy controls and primary neurons, suggesting a pathological connection between the cellular load of the mutant protein and TDP-43 pathology. While the terminal domain of the WT isoform is characterized by an acid isoelectric point (pI), the ALS variant presents a basic pI due to the altered aminoacidic composition of this sequence. We thus generated a KIF5A-ALS isoform that retained part of the aberrant sequence but with lower pI. The overexpression of this mutated variant led to significantly lower protein aggregation and TDP-43 mislocalization than the ALS mutant. Our data show that re-establishing the correct pI rescues KIFA aggregation and significantly reduces the cytoplasmic mislocalization of TDP-43.

ID: 40717725
Title: Thalamic nuclei volumes are related to disease stage in patients with amyotrophic lateral sclerosis.
Abstract: To explore atrophy patterns in thalamic nuclei at different phases of amyotrophic lateral sclerosis (ALS) and determine any correlations between thalamic nucleus volume and either cognitive impairments or motor disabilities. We used the King's clinical staging system for ALS to divide 76 consecutive patients with ALS by disease stage. We investigated patterns of thalamic atrophy in the patients and in 94 healthy controls (HCs). Cognitive functions were evaluated with the Mini-Mental State Examination (MMSE), Frontal Assessment Battery, Boston Naming Test, and Auditory Verbal Learning Test. Considering all ALS patients, no significant differences were observed in the volume of any thalamic nuclei between the ALS group and HCs. Thalamic nucleus volumes remained normal in ALS patients at King's Stage 2 and Stage 3. However, atrophy was detected in the bilateral anteroventral nucleus, bilateral pulvinar-limitans, bilateral mediodorsal-paratenial-reuniens, bilateral motor hub, bilateral sensory hub, and bilateral intralaminar nucleus in patients who had reached King's Stage 3. In these patients, the volume of the bilateral motor nuclei was associated with the revised ALS Functional Rating Scale scores, and that of the right pulvinar-limitans independently correlated with MMSE scores. Our study provides a comprehensive profile of thalamic atrophy in ALS patients. The thalamic atrophy patterns in these patients extremely differs at different King's Stages, and we suggest that these alterations might result largely from sequential, regional patterns of TDP-43 pathology in ALS. Furthermore, thalamic atrophy might play important roles in motor disability and global cognitive impairments observed in patients with ALS.

ID: 40986178
Title: The Present and Future of Monoclonal Antibody Therapies for Multiple Sclerosis.
Abstract: Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system characterized by inflammation, demyelination, and neurodegeneration. Advances in understanding MS immunopathogenesis have led to the development of monoclonal antibodies (MABs) that target key immune pathways, providing highly selective and effective treatment options. Approved MABs, including those against CD20, CD25, CD52, and α4‑integrin, have demonstrated robust efficacy in reducing relapse rates, suppressing MRI activity, and, to some extent, slowing disability progression. Meanwhile, emerging agents aim to modulate neuroinflammation, promote remyelination, and improve safety profiles. This review summarizes the mechanisms of action, clinical efficacy, safety, and future perspectives of MAB therapies in MS, highlighting lessons from discontinued agents and opportunities for next‑generation therapeutics.

ID: 41044342
Title: Muscle-derived miR-126 regulates TDP-43 axonal local synthesis and NMJ integrity in ALS models.
Abstract: Amyotrophic lateral sclerosis (ALS) is characterized by neuromuscular junction (NMJ) disruption and neurodegeneration. Recent findings highlight a pivotal role for TAR DNA-binding protein 43 (TDP-43) in forming axonal pathological condensates and facilitating NMJ disruption through inhibition of local protein synthesis. However, the mechanisms that drive local TDP-43 accumulation remain unknown. Here we identify that the TDP-43 axonal accumulation in peripheral nerves of SOD1 patients and mice stems from its aberrant local synthesis. This is a non-cell-autonomous process driven by muscle-derived miR-126a-5p extracellular vesicles (EVs). Inhibiting muscle secretion of miR-126a-5p prompts presynaptic TDP-43 synthesis and accumulation, which disrupts axonal translation and causes NMJ degeneration. Introducing miR-126 to SOD1G93A mice, primary co-cultures and human induced pluripotent stem cell (iPSC)-derived co-cultures with ALS mutations exhibits neuroprotective effects and delays motor decline. These findings identify a transcellular communication axis between muscles and motor neurons that regulates axonal local synthesis and NMJ maintenance, offering insights into ALS onset and progression.

ID: 41114826
Title: [Objective methods of hearing assessment as a contribution to a scientifically sound expert opinion].
Abstract: Objective hearing test procedures are of great importance in the expert opinion, as their results cannot be manipulated by the person being examined and they increase the correctness, accuracy, diagnostic depth, and forensic quality of an expert opinion. According to the systematic of the ascending processes of hearing, they are divided into tympanometry to examine sound conduction and peripheral neuronal processing in the acoustic reflex; otoacoustic emissions (OAE) to assess the outer hair cells in the inner ear; and the broad field of acoustic evoked potentials (AEPs), which can be used to examine various aspects of neuronal excitation processing from the spiral ganglion to the auditory center. Of all objective methods, AEPs are the most versatile because they can be used to estimate hearing thresholds in air and bone conduction, detect aspects of maturation and deprivation, and assess functional aspects of retrocochlear hearing disorders that can only be examined and detected in this way. Sufficient audiometric knowledge and strict quality assurance are absolute prerequisites for the use of all objective procedures. Objektive Hörprüfungsverfahren haben im Gutachten einen hohen Stellenwert, da ihre Ergebnisse von der zu untersuchenden Person nicht manipulierbar sind, sie erhöhen die Richtigkeit, Genauigkeit und diagnostische Tiefe sowie die forensische Qualität eines Gutachtens. Sie gliedern sich nach der Systematik der aufsteigenden Prozesse des Hörens in die Tympanometrie zur Untersuchung der Schallleitung und der peripheren neuronalen Verarbeitung beim Stapediusreflex, die otoakustischen Emissionen (OAE) zur Beurteilung der äußeren Haarzellen im Innenohr und in das weite Feld der akustisch evozierten Potenziale (AEP), mit denen vielfältige Aspekte der neuronalen Erregungsverarbeitung vom Ganglion spirale bis zum Hörzentrum untersucht werden können. Von allen objektiven Methoden sind die AEP am vielseitigsten einsetzbar, weil mit ihnen eine Hörschwellenschätzung in Luft- und Knochenleitung vorgenommen werden kann, Reifungs- und Deprivationsaspekte nachgewiesen und funktionelle Aspekte bei retrocochleären Hörstörungen beurteilt werden können, die nur damit untersuchbar und nachweisbar sind. Für die Anwendung aller objektiven Verfahren ist eine ausreichende audiometrische Ausbildung und eine strenge Qualitätssicherung unbedingte Voraussetzung.

ID: 41331812
Title: HCMV immediate-early protein IE2 induces neurotoxicity and hearing loss by disrupting TSC2-mTOR signaling and metabolic homeostasis.
Abstract: Sensorineural hearing loss (SNHL) caused by human cytomegalovirus (HCMV) infection involves alterations in both the central auditory pathways and cochlear structures. Immediate early (IE) proteins are critical for HCMV pathogenicity and have been associated with neurodevelopmental disorders; however, their contribution to HCMV-associated SNHL remains unclear. Here, we generated transgenic mouse models expressing HCMV IE1 and IE2 protein to investigate their effects on auditory function and cochlear pathology. Auditory brainstem response (ABR) measurements revealed that expression of IE2, but not IE1, led to significantly elevated ABR thresholds and impaired auditory processing. IE2-transgenic mice exhibited synaptic loss, hair cell degeneration, and neuronal atrophy in auditory regions. scRNA-seq analysis indicated broad activation of inflammatory pathways and cytokines within the cochlea, along with disruptions in mitochondrial and metabolic pathways, suggesting that IE2 may contribute to hearing loss through mitochondrial impairment and inflammation. Transmission electron microscopy of cochlear tissues showed severe morphological abnormalities and a marked reduction in mitochondrial number in spiral ganglion neurons (SGNs). Further mechanistic investigation demonstrated that IE2 interacts with TSC2, leading to hyperactivation of mTOR signaling, metabolic dysregulation, and mitochondrial dysfunction. Importantly, administration of mTOR inhibitors substantially alleviated IE2-induced auditory deficits, hair cell degeneration, and neuronal atrophy. These findings identify IE2 through TSC2-mTOR-mediated mitochondrial dysfunction, metabolic reprogramming, and neuroinflammation leading to SNHL. Our study reveals a previously unrecognized mechanism linking IE2 protein expression to auditory neurodegeneration and suggests mTOR modulation as a potential therapeutic strategy for congenital HCMV infection and associated hearing loss.

ID: 41485061
Title: Calcineurin depletion coincides with phosphorylated TDP-43 deposition in a mouse model of ALS/FTLD-TDP.
Abstract: Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP) exhibit predominantly cytoplasmic phosphorylated inclusions of the protein TDP-43 as the major neuropathological lesion. Phosphorylated TDP-43 can modify protein aggregation and promote neuronal dysfunction and neurodegeneration in models of ALS and FTLD-TDP. The phosphatase calcineurin has previously been shown to directly dephosphorylate TDP-43 in vitro and prevent accumulation of phosphorylated TDP-43 in vivo in C. elegans. However, it is unknown whether dysregulation of calcineurin contributes to increased TDP-43 phosphorylation and neurodegeneration in the mammalian brain. Here we show in an inducible mouse model of ALS/FTLD-TDP driven by expression and cytoplasmic mislocalization of human TDP-43 (rNLS8 mice), calcineurin protein decreases dramatically in the brain. This depletion coincides with increased levels of the TDP-43 kinase CDC7 and accumulation of phosphorylated TDP-43, and precedes frank neurodegeneration. Using brain-wide single nucleus RNA sequencing (snRNAseq) in symptomatic rNLS8 mice, we find cell-type selective reduced expression of catalytic and regulatory subunits of calcineurin predominantly in GABAergic and glutamatergic neurons. In mouse primary neuron culture and C. elegans models of ALS/FTLD-TDP, we demonstrate activation or overexpression of calcineurin protects against accumulation of phosphorylated TDP-43, neurotoxicity, and neurodegeneration. Taken together, our data suggests calcineurin dysregulation may be a major contributor to loss of brain resilience mechanisms against phosphorylated TDP-43. Restoring calcineurin activity may present a new target for intervening in TDP-43 proteinopathies, including ALS and FTLD-TDP.

ID: 41510529
Title: Neuroinvasive West Nile Virus Presenting as Subacute Progressive Quadriparesis and Intractable Pain: A Case Report.
Abstract: West Nile virus (WNV) is the most common mosquito-borne infection in North America; while most cases are asymptomatic, fewer than 1% develop neuroinvasive disease with significant morbidity and mortality. We report a 57-year-old man from rural Wisconsin who presented with a 10-week history of progressive asymmetric quadriparesis and severe intractable pain, preceded by fatigue, shoulder pain, and paresthesias. Neurologic examination demonstrated mild encephalopathy, bulbar involvement, and mixed upper and lower motor neuron signs. MRI showed patchy thoracic cord T2 hyperintensities and diffuse lumbar ventral root enhancement. Electrodiagnostic studies revealed diffuse active denervation and reduced compound muscle action potentials, initially raising concern for amyotrophic lateral sclerosis. Elevated WNV IgM and IgG titers in serum and cerebrospinal fluid confirmed neuroinvasive WNV infection. Despite treatment with corticosteroids and intravenous immunoglobulin, the patient deteriorated and was transitioned to hospice care. Autopsy demonstrated T-cell-mediated meningoencephalitis with widespread lymphocytic inflammation involving motor neurons, spinal cord, ventral rootlets, and peripheral nerves, consistent with diffuse axonopathy. This case underscores that neuroinvasive WNV may closely mimic motor neuron disease and emphasizes the importance of serologic testing for accurate diagnosis. Management remains supportive, and outcomes can be severe due to extensive central and peripheral nervous system involvement.

ID: 41576445
Title: Noise exposure induces autophagy-modulated nuclear-to-cytoplasmic translocation of TDP-43 in spiral ganglion neurons.
Abstract: Noise exposure contributes to approximately one-third of hearing loss cases worldwide. Despite its substantial global burden, noise-induced hearing loss (NIHL) remains essentially irreversible, largely because its underlying pathogenic mechanisms are not yet fully defined. In this study, we established three noise-induced hearing loss mouse models and evaluated auditory function by measuring auditory brainstem response (ABR) thresholds at multiple time points following noise exposure. In parallel, we examined the spatiotemporal redistribution of TDP-43 and evaluated autophagic flux in spiral ganglion neurons (SGNs) to elucidate their dynamic responses to acoustic stress. Noise exposure triggers marked nucleocytoplasmic translocation and cytoplasmic aggregation of TDP-43 in spiral ganglion neurons (SGNs), accompanied by dynamic alterations in autophagic flux. Using pharmacological modulation, we demonstrate that autophagy critically shapes the fate of TDP-43. Mechanistically, noise-induced stressors such as reactive oxygen species (ROS) likely initiate TDP-43 nuclear export, whereas insufficient autophagic flux impedes aggregate degradation and exacerbates cytoplasmic inclusion formation. Together, these findings reveal autophagy as a key determinant of TDP-43 dynamics in the auditory system and identify the autophagy-TDP-43 axis as a potential therapeutic target for preventing or ameliorating noise-induced hearing loss.

ID: 41634873
Title: Chaperone mediated autophagy is deficient in spinal motoneurons of ALS patients with TDP-43 proteinopathy.
Abstract: Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease characterized by the selective loss of motor neurons (MNs), ultimately resulting in paralysis and respiratory failure within 3 to 5 years of onset. Fewer than 10% of ALS cases are familial (fALS), while the vast majority are sporadic (sALS) with an unknown etiology. A pathological hallmark of ALS is the accumulation of misfolded TDP-43 protein aggregates within MNs. Although TDP-43 is known to be degraded via chaperone-mediated autophagy (CMA), the status of CMA activity in sALS has not been previously explored. To investigate this, we analyzed CMA in human spinal cord tissue by assessing the expression of LAMP2A, a key lysosomal receptor and marker of CMA activity. In control samples, spinal cord MNs exhibited robust LAMP2A expression. In contrast, MNs from sALS patients showed a marked reduction in LAMP2A levels, coinciding with the presence of TDP-43 pathology. Notably, analysis of LC3, a marker of macroautophagy, revealed no significant differences in expression between control and sALS MNs. Interestingly, MNs within the Onuf’s nucleus, a population known to be resistant to degeneration in ALS, retained normal LAMP2A expression and did not exhibit TDP-43 aggregation in sALS cases. These findings demonstrated that CMA is essential for the clearance of TDP-43 in spinal cord MNs and that its dysfunction may contribute to the pathogenesis of sALS. Furthermore, the high dependence of spinal cord MNs on CMA activity may underlie their selective vulnerability to degeneration when CMA is impaired, and highlight CMA enhancement as a promising therapeutic strategy to restore proteostasis and prevent MN degeneration in ALS.

ID: 41739359
Title: Neural Hearing Loss: Mechanisms, Diagnosis and Treatment Horizons.
Abstract: Neural hearing loss, characterized by dysfunction of the auditory nerve, including the spiral ganglion neurons (SGNs) and/or their synaptic connections, is increasingly recognized as a critical contributor to auditory deficits across diverse conditions, including Auditory Neuropathy Spectrum Disorder (ANSD), presbycusis, and noise-induced hearing loss (NIHL). It is possible that neural hearing loss is underdiagnosed, due to the lack of clinical tools with sufficient sensitivity and specificity to detect poor neural health. Current interventions, such as hearing aids and cochlear implants (CIs), primarily target sensory deficits and offer limited benefit in cases of significant neural compromise. Therapeutically, there is a growing shift towards biologically driven strategies aimed at restoring neural function. Recent developments in novel therapies, including pharmacological, gene-based, neurotrophic, and cell-based approaches, have opened new possibilities demonstrating the potential to protect, repair, and/or replace damaged SGNs, and re-establish auditory pathways. This perspectives article explores the evolving understanding of neural hearing loss, emphasizing its complex pathophysiology and the limitations of current diagnostic and therapeutic approaches, while highlighting how a diverse range of emerging solutions are moving closer to clinical application.

ID: 42198452
Title: Progressive Sensorineural Hearing Loss Following Cisplatin Chemotherapy: Mechanisms Underlying Cochlear Retention and Long-Term Ototoxicity.
Abstract: Cisplatin-induced ototoxicity is a permanent, bilateral sensorineural hearing loss occurring in up to 80% of treated patients. Its defining and clinically challenging feature is the progressive worsening of auditory function that continues well after chemotherapy has ended, a trajectory that cannot be explained by cumulative dose alone. This article is a comprehensive review of the present research studies on mechanisms that are responsible for this post-treatment progression. The cochlea, unlike other organs, appears to be unable to eliminate platinum (the active divalent metal ion released from cisplatin and responsible for its cytotoxic and ototoxic effects): traces of it can be found in human temporal bone tissue even more than 18 months after last infusion, and bone might serve as a long-term systemic reservoir. Within the inner ear, platinum accumulates preferentially in the stria vascularis, impairing endocochlear potential and outer hair cell function. Retained platinum sustains cascading effects including sustained NOX3-dependent oxidative stress, mitochondrial dysfunction, ongoing genotoxic injury to non-regenerative cells, and the early loss of ribbon synapses that precipitates delayed spiral ganglion neurodegeneration. Pharmacogenetic variability in platinum transport and antioxidant metabolism further modulates individual susceptibility. These findings support lifelong audiological surveillance and provide a basis for designing strategies that can protect hearing without compromising the essential anticancer efficacy of cisplatin therapy.

ID: 42299014
Title: Pathogenic Proteins Driving ALS Pathogenesis: Molecular Mechanisms and Translational Therapeutic Perspectives.
Abstract: Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive degeneration of motor neurons, with protein aggregation as a central pathological hallmark. Key pathogenic proteins, including TDP-43, SOD1, FUS, and dipeptide repeat proteins (DPRs) from C9orf72 expansions, drive disease progression through diverse but converging mechanisms. TDP-43 proteinopathy, present in nearly all ALS cases, involves cytoplasmic mislocalization, misfolding, and aggregation, disrupting RNA processing, protein transport, and DNA repair. Similarly, SOD1 and FUS mutations promote toxic protein aggregation, impairing cellular homeostasis and contributing to neuronal dysfunction. C9orf72-derived DPRs exert toxicity by interfering with nucleocytoplasmic transport. The propagation of these pathogenic proteins between neurons and glia, often via prion-like mechanisms, underlies the characteristic spread of ALS pathology throughout the nervous system. Cellular protective responses, such as molecular chaperones and the ubiquitin-proteasome system, attempt to mitigate aggregation but are often overwhelmed in disease states. Mitochondrial dysfunction, oxidative stress, and disturbances in calcium homeostasis are also implicated, with evidence showing that SOD1 mutations can alter redox balance and mitochondrial function in both neurons and non-neuronal cells. Impaired DNA repair mechanisms, involving proteins such as TDP-43, FUS, NEK1, and VCP, have emerged as important contributors to ALS pathogenesis, linking protein aggregation to genomic instability. Recent therapeutic strategies focus on directly targeting misfolded proteins using small molecules, peptides, or antisense oligonucleotides to inhibit aggregation or enhance clearance, offering hope for disease modification. Understanding the interplay between protein aggregation, impaired RNA metabolism, and cellular stress responses is crucial for developing effective translational therapies for ALS.

ID: 42431902
Title: Molecularly defined auditory neuron subtypes show different vulnerabilities to noise- and age-related synaptopathy in mice.
Abstract: Neuronal subtype-specific synaptopathy is a hallmark of many forms of neurodegeneration. We examined the cellular basis for synaptic vulnerability in the auditory system, where three subtypes of spiral ganglion neurons (SGNs)-Ia, Ib, and Ic-carry acoustic information from the cochlea to the brain. In response to noise and aging, a subset of synapses between inner hair cells and SGNs are lost, but it is unclear how this loss varies across SGN subtypes. Using genetic labeling, we showed that Ia SGNs have larger post-synaptic densities (PSDs) than Ib and Ic SGNs and are the most resilient subtype. Ia PSD volumes increase with age and are unchanged after noise exposure. By contrast, average Ib/Ic PSD volumes do not change with age but decrease with noise. Genetic reprogramming of Ib/Ic neurons to a Ia-like identity provides significant protection against noise-induced synaptopathy, linking identity to resilience and providing an entry point for therapeutics.

ID: 42546774
Title: Catalpol Protects Against MPP+-Induced Neurotoxicity by Targeting PINK1/DJ-1-Mediated Mitophagy and the TrkB/Akt/BDNF/Bcl-2 Axis.
Abstract: Parkinson's disease (PD) is a prevalent neurodegenerative disorder characterized by dopaminergic neuronal death of unclear etiology. While levodopa remains the gold standard for managing PD motor symptoms, it lacks disease-modifying efficacy, necessitating new neuroprotective therapies. Mitochondrial dysfunction and impaired autophagy are key hallmarks of PD. This study utilized 1-methyl-4-phenylpyridinium (MPP+)-treated SH-SY5Y cells to investigate the neuroprotective mechanisms of catalpol, an iridoid glycoside derived from Rehmannia glutinosa. We found that catalpol attenuated MPP+-induced neurotoxicity, mitochondrial membrane depolarization, and ATP depletion. This protection was critically dependent on autophagy; it was enhanced by the activator rapamycin but abolished by the inhibitor wortmannin and the autophagosome-lysosome fusion inhibitor bafilomycin A1. Catalpol activated autophagy by increasing autophagosome formation, elevating Beclin 1 and LC3-II levels, and promoting p62 degradation. Furthermore, catalpol reversed MPP+-induced mitophagy suppression and restored the regulatory protein PINK1 and DJ-1 expression. Given that Akt/BDNF/Bcl-2 and TrkB/BDNF pathways promote neuronal survival, we investigated their involvement. We found that the TrkB agonist 7,8-DHF mimicked catalpol's neuroprotection against MPP+-induced neurotoxicity, whereas the pan-Trk inhibitor GNF-5837 abolished it. Western blotting demonstrated that catalpol reversed MPP+-mediated suppression of TrkB and Akt phosphorylation, as well as BDNF and Bcl-2 expression. Molecular docking indicated that catalpol may interact with the TrkB ligand-binding domain with higher affinity than 7,8-DHF, and shares key binding residues. Our findings suggest that catalpol exerts neuroprotection via a dual mechanism: preserving mitochondrial function through PINK1/DJ-1-mediated mitophagy and activating the TrkB/Akt/BDNF/Bcl-2 survival pathway, potentially by interacting with the TrkB receptor, highlighting its therapeutic potential for PD.

ID: 42549326
Title: Integrated transcriptomic and metabolomic profiling reveals coordinated regulatory networks associated with mosaic disease resistance in sugarcane.
Abstract: Sugarcane mosaic disease (SCMD) poses a severe threat to global sugarcane yield. Since conventional field management is insufficient to restrict viral transmission, unraveling the underlying defense mechanisms is imperative for targeted breeding. The primary objective of this study was to delineate the molecular and metabolic networks governing SCMD resistance by comparing highly resistant (XIDAZHE10-19, YT94-128) and susceptible (HP, XTT22) cultivars. We employed metabolomic profiling and integrated transcriptomic data to investigate the genetic basis driving host responses. To further elucidate the functional and regulatory mechanics of identified key hub genes, we conducted weighted gene co-expression network analysis (WGCNA) alongside AlphaFold-driven structural predictions and interactome profiling. Metabolomic profiling identified critical defense-associated metabolites --including alcoholamines and glycerol derivatives --that strongly correlate with disease incidence. Transcriptomic integration yielded two major findings. First, pathway enrichment revealed a striking dichotomy in defense strategies: XIDAZHE10-19 preferentially orchestrated the autophagy pathway and aromatic amino acid biosynthesis, whereas YT94-128 relied heavily on calcium signaling and peroxisome-mediated reactive oxygen species (ROS) homeostasis. Second, WGCNA pinpointed ShNDK as a core hub gene exhibiting robust upregulation in susceptible cultivars. AlphaFold predictions further revealed that ShNDK potentially assembles into dimers and physically associates with canonical immune transcription factors (e.g., bZIP, Dof) and pathogenesis-related (PR) proteins. The novelty of this work lies in uncovering divergent, cultivar-specific defense strategies and identifying novel genetic hubs through a multi-omics and structural biology approach. Together, these findings unveil a complex, multi-layered defense network against SCMD. The characterization of ShNDK and the elucidation of cultivar-specific synergistic crosstalk provide a crucial mechanistic foundation and promising genetic targets for developing sugarcane cultivars with heritable, broad-spectrum resistance.

ID: 42549868
Title: Vitamin D receptor in intrauterine adhesion: a hypothesis-driven review of potential roles and mechanistic insights.
Abstract: Intrauterine adhesion (IUA) is a fibrotic disorder of the endometrium associated with menstrual disturbance, infertility, recurrent pregnancy loss, and adverse obstetric outcomes. Although surgical adhesiolysis remains the main treatment, recurrence is common, highlighting the need for better understanding of molecular mechanisms underlying endometrial fibrosis and repair. Vitamin D receptor (VDR), a nuclear hormone receptor involved in cell differentiation, immune regulation, autophagy and tissue remodeling, has recently been implicated in IUA pathogenesis. This review summarizes current evidence on VDR expression and function in IUA, with emphasis on its potential regulation of autophagy, epithelial-mesenchymal transition (EMT), and pro-fibrotic mTOR, AKT and MAPK/ERK signaling. Available data suggest that reduced VDR expression in endometrial tissue is associated with increased fibrosis, impaired autophagic flux, p62 accumulation, and EMT activation. However, direct evidence in human IUA and endometrial-specific models remains limited, and much of the mechanistic framework is extrapolated from other fibrotic disease models including kidney, liver and cancer fibrosis. Therefore, VDR should currently be viewed as a biologically plausible regulator and candidate biomarker rather than an established therapeutic target in IUA. We also discuss the potential, but still unproven, role of vitamin D supplementation, VDR agonists and autophagy modulators, as adjunctive strategies. Future studies should validate VDR expression in larger IUA cohorts, develop clinically relevant endometrial models, and test whether VDR-targeted interventions can improve endometrial repair or reduce adhesion recurrence.

ID: 42550094
Title: Physical activity and human IAPP islet amyloidosis: mechanistic plausibility, missing evidence, and future directions.
Abstract: Islet amyloid deposition derived from human islet amyloid polypeptide (hIAPP, amylin) is a hallmark of type 2 diabetes (T2D) and is tightly linked to progressive β-cell dysfunction and loss. It is now well established that the "toxic oligomer" hypothesis, in which soluble or intracellular hIAPP assemblies contribute to β-cell proteotoxicity and to the amplification of inflammatory stress, coexists with fibril associated and inflammation-driven mechanisms of toxicity. Regular physical activity (PA) is a cornerstone of T2D management and improves insulin sensitivity, glycemic control, ectopic lipid handling, and systemic inflammation, all of which could reduce β-cell secretory burden and the cellular milieu that favors hIAPP misfolding. However, direct demonstrations that PA delays or reduces islet amyloid formation remain scarce. This gap largely reflects methodological constrains in quantifying amyloid dynamics in humans and the absence of exercise studies with amyloid-specific endpoints. Herein, we synthesize mechanistic links by which exercise could influence hIAPP aggregation propensity (β-cell workload, glucolipotoxicity, endoplasmic reticulum stress, mitochondrial function, and inflammatory signaling) and highlight proteostasis pathways, particularly autophagy/lysosomal clearance, that are experimentally shown to defend β-cells against hIAPP oligomer toxicity. Overall, while direct evidence remains sparse, substantial mechanistic plausibility supports a link between PA and hIAPP amyloid biology. Future studies incorporating amyloid-specific outcomes are needed to determine whether exercise directly modifies amyloid formation, reduces oligomer burden, or primarily enhances β-cell resilience to proteotoxic stress.

ID: 42551351
Title: Discovery of hydrazone derivatives as novel STAT3 antagonists against pancreatic and colorectal cancers.
Abstract: Signal transducer and activator of transcription 3 (STAT3) has been an anti-cancer protein target for three decades due to its over-activation in various cancers; however, direct STAT3 inhibitors have not reached the market. In this study, a series of novel hydrazone derivatives were designed, synthesized, and characterized. The most promising compound P42 was found to selectively target the STAT3 SH2 domain over the DNA-binding domain, as suggested by the results from fluorescence polarization assays. The GI50 values after 72 h of P42 treatment were determined to be 0.85-5 μM in STAT3-overexpressing pancreatic and colorectal cancer cell lines harboring KRAS mutations (MIA PaCa-2, DLD-1 and HCT 116). Western blot analyses showed that P42 significantly inhibited phosphorylated STAT3 levels without affecting total STAT3 and its upstream kinases JAK2 and SRC. P42 demonstrated significant autophagy-associated cell death rather than apoptosis or necrosis in flow cytometry analyses, with increases in LC3II/I ratios and decreases in p62 levels. Cancer stemness potential was significantly abrogated with P42 as shown in colony formation assay and decreases in epithelial-mesenchymal transition/stemness markers SNAIL and ZEB1 levels. Molecular docking further supported a plausible binding mode within the STAT3 SH2 domain for P42, and SwissADME prediction suggested its favorable drug-likeness properties. Taken together, P42 warrants future anti-cancer drug development.

ID: 42551360
Title: Perfluorooctanoic acid disrupts lysine metabolism and autophagy to promote white spot syndrome virus infection in shrimp.
Abstract: Perfluorooctanoic acid (PFOA), a globally distributed per- and polyfluoroalkyl substance (PFAS), is increasingly recognized for its immunotoxic and metabolic effects in aquatic organisms; however, its role in viral disease susceptibility remains poorly understood. Using Pacific white shrimp (Penaeus vannamei) and white spot syndrome virus (WSSV) as a model system, we investigated the effects of chronic PFOA exposure on antiviral immunity and viral transmission. Chronic exposure to environmentally relevant concentrations of PFOA resulted in significant accumulation of PFOA in the hepatopancreas and markedly increased WSSV replication, host mortality, and horizontal transmission. Integrated metabolomic and transcriptomic analyses identified lysine degradation as a consistently affected metabolic pathway, along with significant enrichment of lysosome-related pathways. Biophysical assays, including molecular docking, biolayer interferometry, and cellular thermal shift analysis, demonstrated that PFOA directly binds to the lysine-catabolizing enzyme aminoadipate semialdehyde synthase (AASS), which may contribute to lysine accumulation. Importantly, enzymatic activity assays further revealed that PFOA significantly inhibited both lysine-ketoglutarate reductase (LKR) and saccharopine dehydrogenase (SDH) activities, accompanied by marked lysine accumulation in shrimp hepatopancreas. PFOA exposure alone induced basal autophagic dysfunction, as evidenced by reduced LC3/LAMP1 co-localization, decreased LC3 abundance, increased p62 accumulation, and impaired autophagosome-lysosome fusion. Dietary lysine supplementation reproduced these autophagic defects and significantly promoted WSSV replication, supporting a role for lysine accumulation in mediating impaired antiviral defense. Together, this study uncovers a previously unrecognized lysine-autophagy-lysosome regulatory axis through which PFOA enhances viral susceptibility and transmission in shrimp, providing mechanistic insight into pollutant-driven disease risk in aquaculture ecosystems.

ID: 42553018
Title: TRAIL PLGA/Gelucire 48/16 and exosome carrier systems enhance anti-tumor efficacy by enabling autophagic motility.
Abstract: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent anticancer protein that selectively reduces the viability of malignant cells but is limited clinically by its short half-life. This study developed novel TRAIL-loaded drug carrier systems to prolong its mean residence time, consequently enhance its biological activity and enhance therapeutic efficacy in breast cancer, and evaluate tumor targeting and modulation of apoptotic and autophagic pathways in vitro and in vivo. TRAIL-loaded carrier systems were prepared using PLGA/Gelucire 48/16 nanoparticles and exosome-based formulations. Following physicochemical characterization, biological effects were assessed in MDA-MB-231 cells and an EAC mouse tumor model, with apoptotic and autophagic responses analyzed by flow cytometry and qPCR. Histopathological assessments included HE staining, TUNEL assay, and Ki-67 IHC. Both PLGA/Gelucire 48/16 nanoparticles and exosome-encapsulated TRAIL significantly suppressed cell viability and enhanced apoptosis in MDA-MB-231 cells. Treatment with these carrier systems upregulated the expression of Caspase-3 and LC3B genes in-vitro and in mouse tumor tissues, indicating activation of apoptotic and autophagic pathways. In the EAC tumor model, TRAIL-loaded formulations reduced tumor growth, decreased the Ki-67 proliferation index, and induced marked tumor regression. Encapsulation of TRAIL in PLGA/Gelucire 48/16 or exosome-based carriers enhances its stability and antitumor activity, highlighting the potential of these carrier platforms to improve TRAIL-encapsulated biotechnological therapeutics for breast cancer treatment.

ID: 42559130
Title: Abnormal auditory neural activity in individuals with spinal muscular atrophy.
Abstract: Spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by hypotonia, progressive muscle weakness and atrophy caused by progressive loss of motor neurons in the spinal cord and lower cranial nerve nuclei. The disease has also been associated with sensory neuropathies affecting the visual, somatosensory and auditory pathways. This case-control study investigated auditory neural function and perceptual ability in children and young adults with SMA. Twenty individuals with genetically confirmed SMA of varying severity (Types 1-3) participated. Sixteen children/young adults aged 6-20 years and 16 age-, gender- and hearing-level matched controls underwent a battery of peripheral and central auditory assessments. These included sound detection measurement, otoacoustic emission and auditory brainstem response testing and speech perception evaluation. In addition, four infants (3-28 months) treated with disease-modifying therapies underwent auditory brainstem response assessment. Despite normal cochlear responses and normal sound detection, most child or young adult participants presented with clinically abnormal auditory neural function and significant speech perception deficits. Auditory brainstem response amplitudes were reduced and latencies increased relative to matched controls (P < 0.005) consistent with axonopathy and/or demyelination in the auditory brainstem. Furthermore, both monaural and binaural speech perception in noise were impaired (P < 0.01) suggesting the presence of significant neural distortion and spatial processing disruption. In contrast, evoked potential findings for our small group of pre-symptomatic infants were normal. The results of this study demonstrate that auditory neural and binaural processing deficits are common in children and young adults with SMA. As such, auditory assessment including auditory brainstem function and speech perception in background noise should be routinely carried out in this population. Interventions specifically designed to improve hearing in background noise (such as remote-microphone listening systems) should be considered to optimize speech/language and psychosocial development and academic outcomes in affected individuals.