# PathMap Report Trace Context: #00000128
Hypothesis: Discovered Hypothesis: Spermidine-mediated autophagic activation may serve as an upstream regulator of lysosomal TMEM175 activity to prevent proteinopathy in C9orf72-ALS/FTD models.
Author: Joshua Dungan (PathMap.org)
License: 'THE GLOBAL HUMANITARIAN PROPRIETARY LICENSE (VERSION 1.0.1)' https://pathmap.org/license.pdf
Full provenance JSON trace: https://pathmap.org/download.php/?id=128
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SYSTEM NOTE: The eight-digit ID numbers (e.g., ID 12345678) used in citations below are PubMed ID numbers and can be loaded via https://pubmed.ncbi.nlm.nih.gov/{ID}/ for verification.

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## Primary Synthesis & Clinical Bottom-Line
Scientific synthesis of geroprotective polyamines and lysosomal ion channel regulation indicates that while both systems are critical for maintaining proteostasis, the specific regulatory axis connecting spermidine-driven autophagy to TMEM175-mediated lysosomal acidification in C9orf72-ALS/FTD pathology remains an unverified, albeit mechanistically sound, cross-talk intersection.

## Plausibility Verdicts
- Evaluation 1: The connection between spermidine and TMEM175 is mechanistically plausible but currently lacks direct empirical evidence.

## Novel & Overlooked Insights
- TMEM175 activity can be synergistically modulated, suggesting complex channel gating that might be responsive to metabolic states influenced by polyamines.
- The C9orf72/SMCR8 complex maintains microglial homeostasis via RAB8A-ESCRT-mediated lysosomal repair, providing a structural repair mechanism distinct from, yet likely coordinated with, macroautophagy.
- Lysosomal membrane damage acts as a specific trigger for ATG8-conjugation, indicating that membrane integrity and ionic flux are tightly coupled through the endo-lysosomal-lipid axis.
- The same galectin axis can amplify neuroinflammation and proteopathic spread in some settings yet support recovery or tissue protection in others, highlighting the context-dependency of lysosomal quality control.
- Protein-layer-dominant autophagy-lysosome remodelling is a feature of dermal fibroblast ageing, suggesting that post-transcriptional control of lysosomal capacity may precede transcriptional changes in systemic aging.

## Extracted Custom Discoveries
### Suggested Experiments
- Assess lysosomal pH in PARK9 iPSC neurons treated with spermidine using LysoDots to observe potential TMEM175-mediated acidification recovery.
- Perform patch-clamp analysis on TMEM175 in spermidine-treated C9ORF72-ALS iPSC-derived motor neurons to determine if polyamine supplementation modulates channel gating.
- Use CRISPR-Cas9 knockdown of TMEM175 in spermidine-treated C9ORF72 models to test if autophagy-induced neuroprotection is dependent on TMEM175.

### Suggested Studies
- Comparative longitudinal study of lysosomal ion channel proteostasis in C9ORF72 and sporadic FTD patient-derived microglia treated with spermidine vs. vehicle.
- Investigation into the impact of polyamine catabolism on lysosomal ion channel composition and ER-lysosome contact site stability.
- Meta-analysis of proteomic datasets focusing on the overlap between spermidine-induced autophagy and membrane-associated ion channel integrity in neurodegeneration.

### Swansons Literature Based Discovery Candidates
- Spermidine-mediated autophagic flux enhances lysosomal membrane integrity through the upregulation of V-ATPase-TMEM175 ion exchange coupling in neurodegenerative models.
- Spermidine is a potent autophagy inducer that modulates histone acetylation and autophagic gene expression (ID: 42588134).
- TMEM175 and V-ATPase complex assembly are critical regulators of lysosomal acidification and pH homeostasis (ID: 42555719; ID: 42553289).
- TFEB, the master transcription factor for lysosomal biogenesis, whose activation is regulated by both spermidine (via autophagy/acetylation) and luminal lysosomal status (via V-ATPase).
- Spermidine-induced TFEB activation likely enhances lysosomal gene expression, potentially including TMEM175 and V-ATPase components, thereby reinforcing the ion channel machinery required for lysosomal pH homeostasis during proteotoxic stress.

### Contradictions Between Evidences
- No direct contradiction exists, though studies on Spermidine emphasize autophagy while studies on TMEM175 emphasize ion flux; the bridge between them remains inferred from shared upstream regulators like TFEB.

### Repurposed Solutions
- Repurposing spermidine as a priming agent to restore ionic homeostasis in TMEM175-deficient models, or using TMEM175 activators like DCPIB in combination with spermidine to amplify autophagic flux.

## Evaluation Scoring Reference
All analyzed perspectives utilize a standardized 1-7 scoring framework:
- Alignment Score (1-7): How well does the evaluated claim factually align with the provided evidence set?
  [1 = Evidence proves claim strictly false, 2 = Evidence indicates the claim is impossible, 3 = Implausible, 4 = Neutral/Unrelated, 5 = Plausible, 6 = Evidence indicates inevitable, 7 = Evidence proves claim strictly true]
- Consilience Score (1-7): How consilient (in agreement) is the evidence set regarding this claim?
  [1 = Highly Conflicting/Disputed, 4 = Mixed, 7 = Unanimous Agreement]
- Confidence Score (1-7): Implied confidence of the research based on study design and depth.
  [1 = In Vitro/Animal/Preprint, 4 = Observational/Moderate, 7 = Meta-analysis/RCT]

## Evaluated Perspectives & Findings
### Perspective R1: Claim [Run1 Eval1 Synthesis] evaluated against Evidence [N/A]
- Alignment Score: 5/7
- Consilience Score: 6/7
- Directional Logic: High Score = SUPPORTS Original Claim
Even though this fact check looked at unique up-to-date abstracts, new evidence may refute this answer in the future. Although 'Zero Hallucinated Moneyshot Quotes' is programmatically enforced, AI is not always immune to inadvertently/erroneously misinterpreting data. This is not medical or professional advice, but instead, is an opinion calculated by AI based on the literature evaluated.

### [CLAIM EVALUATED AND ANSWER TO USER]
"Discovered Hypothesis: Spermidine-mediated autophagic activation may serve as an upstream regulator of lysosomal TMEM175 activity to prevent proteinopathy in C9orf72-ALS/FTD models."

The proposed hypothesis that spermidine-mediated autophagic activation functions as an upstream regulator of TMEM175 activity to prevent proteinopathy in C9orf72-ALS/FTD models is biologically plausible based on the convergence of identified cellular pathways; however, the provided literature lacks explicit experimental confirmation of a direct causal link between spermidine-induced autophagy and TMEM175 channel modulation. The dataset confirms that spermidine induces autophagy via EP300 inhibition and other mechanisms, and that TMEM175 dysregulation contributes to neurodegenerative pathogenesis, yet the two are not explicitly linked in the current corpus.

### [ABSTRACT & REWRITTEN CLAIM]
Scientific synthesis of geroprotective polyamines and lysosomal ion channel regulation indicates that while both systems are critical for maintaining proteostasis, the specific regulatory axis connecting spermidine-driven autophagy to TMEM175-mediated lysosomal acidification in C9orf72-ALS/FTD pathology remains an unverified, albeit mechanistically sound, cross-talk intersection.

### [INTRODUCTION & JUSTIFICATION]
Lysosomal dysfunction is recognized as a fundamental driver of neurodegenerative pathology. Spermidine, a dietary polyamine, induces autophagy through EP300 inhibition and is associated with reduced all-cause mortality in prospective studies. Autophagic pathways, including those maintained by the C9orf72/SMCR8 complex, are vital for microglial homeostasis and lysosomal repair. Simultaneously, TMEM175 serves as a lysosomal cation channel essential for maintaining lysosomal pH and function. Dysregulation of the autophagy-lysosomal pathway is a converging mechanism of pathology in C9orf72-associated diseases. While evidence indicates that pharmacological activation of autophagy can mitigate DPR accumulation and proteostatic stress in C9orf72 models, a direct regulatory relationship between spermidine and the TMEM175 channel remains a high-potential hypothesis for future investigation.

### [DISCUSSION: NOVEL & OVERLOOKED]
*   TMEM175 activity can be synergistically modulated, suggesting complex channel gating that might be responsive to metabolic states influenced by polyamines.
*   The C9orf72/SMCR8 complex maintains microglial homeostasis via RAB8A-ESCRT-mediated lysosomal repair, providing a structural repair mechanism distinct from, yet likely coordinated with, macroautophagy.
*   Lysosomal membrane damage acts as a specific trigger for ATG8-conjugation, indicating that membrane integrity and ionic flux are tightly coupled through the endo-lysosomal-lipid axis.
*   The same galectin axis can amplify neuroinflammation and proteopathic spread in some settings yet support recovery or tissue protection in others, highlighting the context-dependency of lysosomal quality control.
*   Protein-layer-dominant autophagy-lysosome remodelling is a feature of dermal fibroblast ageing, suggesting that post-transcriptional control of lysosomal capacity may precede transcriptional changes in systemic aging.

### [EVIDENCE, METHODOLOGY & CITATIONS]
1. ID: 42588134 - Application: Spermidine mechanism of action - "Spermidine, a dietary polyamine from wheat germ and fermented foods, induces autophagy through EP300 inhibition and is associated with reduced all-cause mortality in prospective studies."
2. ID: 42215790 - Application: C9orf72/SMCR8 lysosomal homeostasis - "The C9orf72/SMCR8 complex maintains microglial homeostasis via RAB8A-ESCRT-mediated lysosomal repair."
3. ID: 42596071 - Application: Membrane repair mechanisms - "Endolysosomal membranes are frequently damaged by pathogenic stress associated with aging, infection, and neurodegeneration, and failure to repair such damage leads to inflammation and cell death."
4. ID: 42596071 - Application: Sensor complexes - "Two E3-like ligase complexes, ATG16L1-ATG5-ATG12 and TECPR1-ATG5-ATG12, act as complementary sensors of lysosomal injury by detecting distinct physicochemical cues, including proton gradient collapse and lipid scrambling."
5. ID: 42512450 - Application: Common axis in neurodegeneration - "New evidence highlights how lysosomal dysfunction, endoplasmic reticulum stress, and microglial activation, act as a common axis in neurodegeneration."
6. ID: 42589464 - Application: Proteomic remodeling - "These results support protein-layer-dominant autophagy-lysosome remodelling as a feature of dermal fibroblast ageing and suggest a cell-type-resolved computational route from ageing proteomics to testable dietary candidates."
7. ID: 42468217 - Application: Spermidine rescue - "Spermidine supplementation effectively restored autophagic activity and rescued the associated cellular defects, thereby improving both nuclear and cytoplasmic maturation in oocytes."
8. ID: 42331842 - Application: Polyamine and autophagy mechanism - "In trophoblast cells, spermidine induces autophagy via hypusination of eukaryotic translation initiation factor 5 A (EIF5A), reducing estrogen and prostaglandin production."
9. ID: 42578565 - Application: HDL and lysosome crosstalk - "HDL-bound endotoxin is degraded through the endosome-lysosome pathway in an SR-B1-dependent manner, attenuating IL-1β activation."
10. ID: 42387584 - Application: SGK1 and microglial phagocytosis - "SGK1 appeared to promote lipid accumulation in microglia by suppressing lipophagy, thereby impairing the ability of microglia to clear cellular debris."
11. ID: 42353250 - Application: Therapeutic targets - "Therapeutic strategies targeting repeated RNA, DPR productions, proteostasis, autophagy, and neuroinflammatory pathways were also discussed."
12. ID: 42385702 - Application: TOP1 and DNA repair - "Rapid approach to DNA adduct recovery (RADAR) assays confirmed increased TOP1-DNA covalent complexes, and duplex sequencing confirmed the increased sIndels and identified single-strand events as likely precursor lesions."
13. ID: 42092406 - Application: TRIM16 role - "TRIM16 mediated the ubiquitination of TFR1 and targeted it for p62-dependent autophagic degradation, which in turn reduced iron accumulation and lipid peroxidation."
14. ID: 42392052 - Application: Ferroptotic stress - "Mechanistically, spermidine depletion suppresses mitochondrial autophagy, promotes mitochondrial peroxidative stress, and increases ferroptotic stress in HSCs."
15. ID: 42266427 - Application: Shared pathology - "Our findings contribute to the understanding of limbic-predominant age-related TDP-43 encephalopathy neuropathologic change genetics and suggest shared biological processes between limbic-predominant age-related TDP-43 encephalopathy neuropathologic change and Alzheimer's disease."
16. ID: 42541426 - Application: Neuroprotection - "Our results suggest that spermidine at low doses has the potential to be a general-purpose neuroprotector."
17. ID: 42506061 - Application: Model strategy - "Rather than seeking a single "best" model, a more productive strategy is to adopt model portfolios tailored to specific biological questions and to integrate mouse studies with human cellular models, postmortem tissue, omics approaches, and biomarker-based validation."
18. ID: 42427771 - Application: NORAD-pumilio axis - "NORAD depletion reduced tau seeding and uptake, whereas functional depletion of PUM1 or PUM2 increased both processes, supporting an antagonistic relationship between NORAD and pumilio signaling in modulation of tau aggregation."
19. ID: 42456394 - Application: Lysosomal acidification - "Enhancing lysosomal acidification and degradative function may help re-establish effective autophagic flux and improve disease outcomes."
20. ID: 42555669 - Application: Glial toxicity - "We find that as with neurons, the GR and G4C2 transgenes produce the highest degree of toxicity when expressed in glia."
21. ID: 42222188 - Application: PQQ and SPD comparison - "PQQ primarily functions as a mitochondrial and redox regulator, enhancing mitochondrial biogenesis and bioenergetic capacity through the AMP-activated protein kinase (AMPK) and sirtuin1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator 1-alpha pathways."
22. ID: 42222188 - Application: SPD mechanism - "In contrast, SPD acts as a key regulator of cellular quality control by inducing macroautophagy and preserving proteostasis, largely through modulation of histone and autophagy-related protein acetylation."
23. ID: 42442908 - Application: ESCRT and neurodegeneration - "Disruption of this ESCRT-autophagy interface has emerged as a common pathological feature across major neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis/frontotemporal dementia."
24. ID: 42494065 - Application: IL17A neutralization - "Therapeutic neutralization of IL17A with a monoclonal antibody (IL17A mAb) ameliorates disease phenotypes in R6/2 HD mice, improving motor performance, extending survival, and reducing gliosis."
25. ID: 42454472 - Application: HCQ and heart - "HCQ exerts multiple beneficial cardiovascular effects through anti-inflammatory, antithrombotic, metabolic, and endothelial-protective mechanisms."
26. ID: 42365390 - Application: Lysophagy protection - "Mechanistically, we identified a protective signaling axis involving p38 MAPK, MK2, and HSP27 that senses ANXA11-induced lysosomal damage and initiates lysophagy."
27. ID: 42167675 - Application: TDP-43 pathophysiology - "TDP-43 mislocalization, post-translational modifications, and aggregation potentiate neuronal loss through disruption of RNA metabolism, nucleocytoplasmic transport, and protein homeostasis."
28. ID: 42510554 - Application: AKU pathology - "The progressive collapse of these adaptive mechanisms may contribute to chondrocyte degeneration and to the pathogenesis of cartilage damage in AKU."
29. ID: 42410910 - Application: LAMP3 function - "Functionally, LAMP3 overexpression alleviated NaIO3-induced LMP, improved lysosomal function, and alleviated autophagic impairment."
30. ID: 42467639 - Application: TFEB modulation - "Levacetylleucine rapidly alters TFEB translocation between the cytoplasm and the nucleus in a biphasic, homeostasis-restoring manner."
31. ID: 42607684 - Application: Sequestration of RhoA - "Unexpectedly, these structures are found to control cytoplasmic signaling through FAM134B/C-mediated lysosomal sequestration of RhoA."
32. ID: 42423109 - Application: BAG3 role - "BCL2-associated athanogene 3 (BAG3) protein has a role in initiating the ALP."
33. ID: 42097046 - Application: BAG3 phenotype - "Expression of BAG3V468M induces a DCM-like phenotype in vivo associated with disrupted myocardial architecture and altered proteostasis."
34. ID: 42561943 - Application: LAMP2-A vesicles - "All bvFTD iMG had fewer LAMP2-A-positive vesicles compared to control iMG."
35. ID: 42549514 - Application: LAPTM4A - "LAPTM4A (lysosome-associated protein transmembrane 4 alpha) stood out as a significant protective lysosome-localized protein from the screening."
36. ID: 42605115 - Application: LysoDots - "These findings highlight the potential of LysoDots as a biocompatible, photostable, multi-functional nanomaterial for long-term monitoring of lysosomal dynamics and cellular homeostasis."
37. ID: 42494065 - Application: Neuroprotective signaling - "IL17A mAb also attenuates mHTT aggregation and enhances neuroprotective signaling, as evidenced by increased expression of DLG4/PSD-95, phosphorylated CREB1, and BDNF."
38. ID: 42247713 - Application: Protein-as-pathogen - "The 'protein-as-pathogen' model, where shed viral proteins act as soluble neurotoxins, is now central to understanding this phenomenon."
39. ID: 42353250 - Application: Biomarkers - "In addition, the potentials of fluid biomarkers, including cerebrospinal fluid poly (GP) and blood neurofilament light chain (NfL), for diagnosis, disease monitoring, and therapeutic assessment were shown."
40. ID: 42598912 - Application: NMR ALP steady-state - "Under basal conditions, NMR skin fibroblasts exhibit a greater abundance of LC3-positive structures than HeLa cells, together with a mixed population of autophagosomes and autolysosomes, indicating a distinct steady-state organisation of the ALP."
41. ID: 42423109 - Application: Increased autophagic flux - "In addition, the LC-II/I ratio increased, indicating increased autophagic flux."
42. ID: 42555719 - Application: V-ATPase assembly - "Mechanistically, GCGR loss disrupts its association with the V-ATPase V1A subunit ATP6V1A, compromises V1-V0 assembly, and thereby impairs lysosomal acidification."
43. ID: 42458574 - Application: BafA1 effect - "Moreover, treatment with the V-ATPase inhibitor BafA1 aggregated cellular senescence phenotype and autophagy inhibition and this phenomenon partially reversed by ATP6V1A overexpression."
44. ID: 42464356 - Application: Microglia engraftment - "We find that engraftment of wild-type, but not Grn-deficient, human microglia restore brain-wide progranulin levels, normalize microglial transcriptional states, and ameliorate pathological, functional, and behavioral phenotypes associated with progranulin loss."
45. ID: 42163657 - Application: Neuroprotective substances - "Neuroprotective effects of such substances as spermidine, urolithin A, resveratrol, αlipoic acid, MitoQ, SkQ1, or CoQ10 have been shown using preclinical research."
46. ID: 42035925 - Application: Galectin paradox - "Importantly, this review highlights a stage- and context-dependent paradox in which the same galectin axis can amplify neuroinflammation and proteopathic spread in some settings yet support recovery or tissue protection in others."
47. ID: 42523377 - Application: Neuronal vulnerability - "By relating neighborhood-level depletion in disease to gene expression in controls, we found that baseline cellular respiration and ATP synthesis predict neuronal vulnerability in disease."
48. ID: 42587389 - Application: TE transcript patterns - "Together, these data provide novel insight into TE transcript dynamics in microglia, highlighting TE transcript patterns that differ from those observed in whole-brain samples and other cell types in aging and AD."
49. ID: 42353250 - Application: C9ORF72 pathology - "C9ORF72 LOF disrupted lysosomal and autophagic pathways in microglia, impairing the immune homeostasis."
50. ID: 42456394 - Application: Lysosomal flux - "Enhancing lysosomal acidification and degradative function may help re-establish effective autophagic flux and improve disease outcomes."



## Logical Systems Map (Logical Gates)
- "Spermidine" -> "Autophagy"
- "Autophagy" -> "Lysosomal Integrity"
- "Lysosomal Integrity" -> "TMEM175"

## Verified Verbatim Quotes
- "Spermidine, a dietary polyamine from wheat germ and fermented foods, induces autophagy through EP300 inhibition and is associated with reduced all-cause mortality in prospective studies."
- "C9ORF72 LOF disrupted lysosomal and autophagic pathways in microglia, impairing the immune homeostasis."
- "These results support protein-layer-dominant autophagy-lysosome remodelling as a feature of dermal fibroblast ageing and suggest a cell-type-resolved computational route from ageing proteomics to testable dietary candidates."
- "Spermidine supplementation effectively restored autophagic activity and rescued the associated cellular defects, thereby improving both nuclear and cytoplasmic maturation in oocytes."
- "In trophoblast cells, spermidine induces autophagy via hypusination of eukaryotic translation initiation factor 5 A (EIF5A), reducing estrogen and prostaglandin production."
- "Endolysosomal membranes are frequently damaged by pathogenic stress associated with aging, infection, and neurodegeneration, and failure to repair such damage leads to inflammation and cell death."
- "HDL-bound endotoxin is degraded through the endosome-lysosome pathway in an SR-B1-dependent manner, attenuating IL-1β activation."
- "New evidence highlights how lysosomal dysfunction, endoplasmic reticulum stress, and microglial activation, act as a common axis in neurodegeneration."
- "SGK1 appeared to promote lipid accumulation in microglia by suppressing lipophagy, thereby impairing the ability of microglia to clear cellular debris."
- "Therapeutic strategies targeting repeated RNA, DPR productions, proteostasis, autophagy, and neuroinflammatory pathways were also discussed."
- "Rapid approach to DNA adduct recovery (RADAR) assays confirmed increased TOP1-DNA covalent complexes, and duplex sequencing confirmed the increased sIndels and identified single-strand events as likely precursor lesions."
- "TRIM16 mediated the ubiquitination of TFR1 and targeted it for p62-dependent autophagic degradation, which in turn reduced iron accumulation and lipid peroxidation."
- "Mechanistically, spermidine depletion suppresses mitochondrial autophagy, promotes mitochondrial peroxidative stress, and increases ferroptotic stress in HSCs."
- "Our findings contribute to the understanding of limbic-predominant age-related TDP-43 encephalopathy neuropathologic change genetics and suggest shared biological processes between limbic-predominant age-related TDP-43 encephalopathy neuropathologic change and Alzheimer's disease."
- "Our results suggest that spermidine at low doses has the potential to be a general-purpose neuroprotector."
- "Rather than seeking a single "best" model, a more productive strategy is to adopt model portfolios tailored to specific biological questions and to integrate mouse studies with human cellular models, postmortem tissue, omics approaches, and biomarker-based validation."
- "NORAD depletion reduced tau seeding and uptake, whereas functional depletion of PUM1 or PUM2 increased both processes, supporting an antagonistic relationship between NORAD and pumilio signaling in modulation of tau aggregation."
- "Enhancing lysosomal acidification and degradative function may help re-establish effective autophagic flux and improve disease outcomes."
- "We find that as with neurons, the GR and G4C2 transgenes produce the highest degree of toxicity when expressed in glia."
- "PQQ primarily functions as a mitochondrial and redox regulator, enhancing mitochondrial biogenesis and bioenergetic capacity through the AMP-activated protein kinase (AMPK) and sirtuin1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator 1-alpha pathways."
- "In contrast, SPD acts as a key regulator of cellular quality control by inducing macroautophagy and preserving proteostasis, largely through modulation of histone and autophagy-related protein acetylation."
- "Disruption of this ESCRT-autophagy interface has emerged as a common pathological feature across major neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis/frontotemporal dementia."
- "Therapeutic neutralization of IL17A with a monoclonal antibody (IL17A mAb) ameliorates disease phenotypes in R6/2 HD mice, improving motor performance, extending survival, and reducing gliosis."
- "HCQ exerts multiple beneficial cardiovascular effects through anti-inflammatory, antithrombotic, metabolic, and endothelial-protective mechanisms."
- "Mechanistically, we identified a protective signaling axis involving p38 MAPK, MK2, and HSP27 that senses ANXA11-induced lysosomal damage and initiates lysophagy."
- "TDP-43 mislocalization, post-translational modifications, and aggregation potentiate neuronal loss through disruption of RNA metabolism, nucleocytoplasmic transport, and protein homeostasis."
- "The progressive collapse of these adaptive mechanisms may contribute to chondrocyte degeneration and to the pathogenesis of cartilage damage in AKU."
- "Functionally, LAMP3 overexpression alleviated NaIO3-induced LMP, improved lysosomal function, and alleviated autophagic impairment."
- "Levacetylleucine rapidly alters TFEB translocation between the cytoplasm and the nucleus in a biphasic, homeostasis-restoring manner."
- "Unexpectedly, these structures are found to control cytoplasmic signaling through FAM134B/C-mediated lysosomal sequestration of RhoA."
- "BCL2-associated athanogene 3 (BAG3) protein has a role in initiating the ALP."
- "Expression of BAG3V468M induces a DCM-like phenotype in vivo associated with disrupted myocardial architecture and altered proteostasis."
- "All bvFTD iMG had fewer LAMP2-A-positive vesicles compared to control iMG."
- "LAPTM4A (lysosome-associated protein transmembrane 4 alpha) stood out as a significant protective lysosome-localized protein from the screening."
- "These findings highlight the potential of LysoDots as a biocompatible, photostable, multi-functional nanomaterial for long-term monitoring of lysosomal dynamics and cellular homeostasis."
- "Spermidine, a dietary polyamine from wheat germ and fermented foods, induces autophagy through EP300 inhibition and is associated with reduced all-cause mortality in prospective studies."
- "In contrast, SPD acts as a key regulator of cellular quality control by inducing macroautophagy and preserving proteostasis, largely through modulation of histone and autophagy-related protein acetylation."
- "Endolysosomal membranes are frequently damaged by pathogenic stress associated with aging, infection, and neurodegeneration, and failure to repair such damage leads to inflammation and cell death."
- "New evidence highlights how lysosomal dysfunction, endoplasmic reticulum stress, and microglial activation, act as a common axis in neurodegeneration."
- "Enhancing lysosomal acidification and degradative function may help re-establish effective autophagic flux and improve disease outcomes."
- "C9ORF72 LOF disrupted lysosomal and autophagic pathways in microglia, impairing the immune homeostasis."
- "The C9orf72/SMCR8 complex maintains microglial homeostasis via RAB8A-ESCRT-mediated lysosomal repair."
- "Two E3-like ligase complexes, ATG16L1-ATG5-ATG12 and TECPR1-ATG5-ATG12, act as complementary sensors of lysosomal injury by detecting distinct physicochemical cues, including proton gradient collapse and lipid scrambling."
- "These results support protein-layer-dominant autophagy-lysosome remodelling as a feature of dermal fibroblast ageing and suggest a cell-type-resolved computational route from ageing proteomics to testable dietary candidates."
- "Spermidine supplementation effectively restored autophagic activity and rescued the associated cellular defects, thereby improving both nuclear and cytoplasmic maturation in oocytes."
- "In trophoblast cells, spermidine induces autophagy via hypusination of eukaryotic translation initiation factor 5 A (EIF5A), reducing estrogen and prostaglandin production."
- "HDL-bound endotoxin is degraded through the endosome-lysosome pathway in an SR-B1-dependent manner, attenuating IL-1β activation."
- "SGK1 appeared to promote lipid accumulation in microglia by suppressing lipophagy, thereby impairing the ability of microglia to clear cellular debris."
- "Therapeutic strategies targeting repeated RNA, DPR productions, proteostasis, autophagy, and neuroinflammatory pathways were also discussed."
- "Rapid approach to DNA adduct recovery (RADAR) assays confirmed increased TOP1-DNA covalent complexes, and duplex sequencing confirmed the increased sIndels and identified single-strand events as likely precursor lesions."
- "TRIM16 mediated the ubiquitination of TFR1 and targeted it for p62-dependent autophagic degradation, which in turn reduced iron accumulation and lipid peroxidation."
- "Mechanistically, spermidine depletion suppresses mitochondrial autophagy, promotes mitochondrial peroxidative stress, and increases ferroptotic stress in HSCs."
- "Our findings contribute to the understanding of limbic-predominant age-related TDP-43 encephalopathy neuropathologic change genetics and suggest shared biological processes between limbic-predominant age-related TDP-43 encephalopathy neuropathologic change and Alzheimer's disease."
- "Our results suggest that spermidine at low doses has the potential to be a general-purpose neuroprotector."
- "Rather than seeking a single "best" model, a more productive strategy is to adopt model portfolios tailored to specific biological questions and to integrate mouse studies with human cellular models, postmortem tissue, omics approaches, and biomarker-based validation."
- "NORAD depletion reduced tau seeding and uptake, whereas functional depletion of PUM1 or PUM2 increased both processes, supporting an antagonistic relationship between NORAD and pumilio signaling in modulation of tau aggregation."
- "We find that as with neurons, the GR and G4C2 transgenes produce the highest degree of toxicity when expressed in glia."
- "PQQ primarily functions as a mitochondrial and redox regulator, enhancing mitochondrial biogenesis and bioenergetic capacity through the AMP-activated protein kinase (AMPK) and sirtuin1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator 1-alpha pathways."
- "Disruption of this ESCRT-autophagy interface has emerged as a common pathological feature across major neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis/frontotemporal dementia."
- "Therapeutic neutralization of IL17A with a monoclonal antibody (IL17A mAb) ameliorates disease phenotypes in R6/2 HD mice, improving motor performance, extending survival, and reducing gliosis."
- "HCQ exerts multiple beneficial cardiovascular effects through anti-inflammatory, antithrombotic, metabolic, and endothelial-protective mechanisms."
- "Mechanistically, we identified a protective signaling axis involving p38 MAPK, MK2, and HSP27 that senses ANXA11-induced lysosomal damage and initiates lysophagy."
- "TDP-43 mislocalization, post-translational modifications, and aggregation potentiate neuronal loss through disruption of RNA metabolism, nucleocytoplasmic transport, and protein homeostasis."
- "The progressive collapse of these adaptive mechanisms may contribute to chondrocyte degeneration and to the pathogenesis of cartilage damage in AKU."
- "Functionally, LAMP3 overexpression alleviated NaIO3-induced LMP, improved lysosomal function, and alleviated autophagic impairment."
- "Levacetylleucine rapidly alters TFEB translocation between the cytoplasm and the nucleus in a biphasic, homeostasis-restoring manner."
- "Unexpectedly, these structures are found to control cytoplasmic signaling through FAM134B/C-mediated lysosomal sequestration of RhoA."
- "BCL2-associated athanogene 3 (BAG3) protein has a role in initiating the ALP."
- "Expression of BAG3V468M induces a DCM-like phenotype in vivo associated with disrupted myocardial architecture and altered proteostasis."
- "All bvFTD iMG had fewer LAMP2-A-positive vesicles compared to control iMG."
- "LAPTM4A (lysosome-associated protein transmembrane 4 alpha) stood out as a significant protective lysosome-localized protein from the screening."
- "These findings highlight the potential of LysoDots as a biocompatible, photostable, multi-functional nanomaterial for long-term monitoring of lysosomal dynamics and cellular homeostasis."
- "IL17A mAb also attenuates mHTT aggregation and enhances neuroprotective signaling, as evidenced by increased expression of DLG4/PSD-95, phosphorylated CREB1, and BDNF."
- "The 'protein-as-pathogen' model, where shed viral proteins act as soluble neurotoxins, is now central to understanding this phenomenon."
- "In addition, the potentials of fluid biomarkers, including cerebrospinal fluid poly (GP) and blood neurofilament light chain (NfL), for diagnosis, disease monitoring, and therapeutic assessment were shown."
- "Under basal conditions, NMR skin fibroblasts exhibit a greater abundance of LC3-positive structures than HeLa cells, together with a mixed population of autophagosomes and autolysosomes, indicating a distinct steady-state organisation of the ALP."
- "In addition, the LC-II/I ratio increased, indicating increased autophagic flux."
- "Mechanistically, GCGR loss disrupts its association with the V-ATPase V1A subunit ATP6V1A, compromises V1-V0 assembly, and thereby impairs lysosomal acidification."
- "Moreover, treatment with the V-ATPase inhibitor BafA1 aggregated cellular senescence phenotype and autophagy inhibition and this phenomenon partially reversed by ATP6V1A overexpression."
- "We find that engraftment of wild-type, but not Grn-deficient, human microglia restore brain-wide progranulin levels, normalize microglial transcriptional states, and ameliorate pathological, functional, and behavioral phenotypes associated with progranulin loss."
- "Neuroprotective effects of such substances as spermidine, urolithin A, resveratrol, αlipoic acid, MitoQ, SkQ1, or CoQ10 have been shown using preclinical research."
- "Importantly, this review highlights a stage- and context-dependent paradox in which the same galectin axis can amplify neuroinflammation and proteopathic spread in some settings yet support recovery or tissue protection in others."
- "By relating neighborhood-level depletion in disease to gene expression in controls, we found that baseline cellular respiration and ATP synthesis predict neuronal vulnerability in disease."
- "Together, these data provide novel insight into TE transcript dynamics in microglia, highlighting TE transcript patterns that differ from those observed in whole-brain samples and other cell types in aging and AD."
- "Spermidine, a dietary polyamine from wheat germ and fermented foods, induces autophagy through EP300 inhibition and is associated with reduced all-cause mortality in prospective studies."
- "In contrast, SPD acts as a key regulator of cellular quality control by inducing macroautophagy and preserving proteostasis, largely through modulation of histone and autophagy-related protein acetylation."
- "Endolysosomal membranes are frequently damaged by pathogenic stress associated with aging, infection, and neurodegeneration, and failure to repair such damage leads to inflammation and cell death."
- "New evidence highlights how lysosomal dysfunction, endoplasmic reticulum stress, and microglial activation, act as a common axis in neurodegeneration."
- "Enhancing lysosomal acidification and degradative function may help re-establish effective autophagic flux and improve disease outcomes."
- "C9ORF72 LOF disrupted lysosomal and autophagic pathways in microglia, impairing the immune homeostasis."
- "The C9orf72/SMCR8 complex maintains microglial homeostasis via RAB8A-ESCRT-mediated lysosomal repair."
- "Two E3-like ligase complexes, ATG16L1-ATG5-ATG12 and TECPR1-ATG5-ATG12, act as complementary sensors of lysosomal injury by detecting distinct physicochemical cues, including proton gradient collapse and lipid scrambling."
- "These results support protein-layer-dominant autophagy-lysosome remodelling as a feature of dermal fibroblast ageing and suggest a cell-type-resolved computational route from ageing proteomics to testable dietary candidates."
- "Spermidine supplementation effectively restored autophagic activity and rescued the associated cellular defects, thereby improving both nuclear and cytoplasmic maturation in oocytes."
- "In trophoblast cells, spermidine induces autophagy via hypusination of eukaryotic translation initiation factor 5 A (EIF5A), reducing estrogen and prostaglandin production."
- "HDL-bound endotoxin is degraded through the endosome-lysosome pathway in an SR-B1-dependent manner, attenuating IL-1β activation."
- "SGK1 appeared to promote lipid accumulation in microglia by suppressing lipophagy, thereby impairing the ability of microglia to clear cellular debris."
- "Therapeutic strategies targeting repeated RNA, DPR productions, proteostasis, autophagy, and neuroinflammatory pathways were also discussed."
- "Rapid approach to DNA adduct recovery (RADAR) assays confirmed increased TOP1-DNA covalent complexes, and duplex sequencing confirmed the increased sIndels and identified single-strand events as likely precursor lesions."
- "TRIM16 mediated the ubiquitination of TFR1 and targeted it for p62-dependent autophagic degradation, which in turn reduced iron accumulation and lipid peroxidation."
- "Mechanistically, spermidine depletion suppresses mitochondrial autophagy, promotes mitochondrial peroxidative stress, and increases ferroptotic stress in HSCs."
- "Our findings contribute to the understanding of limbic-predominant age-related TDP-43 encephalopathy neuropathologic change genetics and suggest shared biological processes between limbic-predominant age-related TDP-43 encephalopathy neuropathologic change and Alzheimer's disease."
- "Our results suggest that spermidine at low doses has the potential to be a general-purpose neuroprotector."
- "Rather than seeking a single "best" model, a more productive strategy is to adopt model portfolios tailored to specific biological questions and to integrate mouse studies with human cellular models, postmortem tissue, omics approaches, and biomarker-based validation."
- "NORAD depletion reduced tau seeding and uptake, whereas functional depletion of PUM1 or PUM2 increased both processes, supporting an antagonistic relationship between NORAD and pumilio signaling in modulation of tau aggregation."
- "We find that as with neurons, the GR and G4C2 transgenes produce the highest degree of toxicity when expressed in glia."
- "PQQ primarily functions as a mitochondrial and redox regulator, enhancing mitochondrial biogenesis and bioenergetic capacity through the AMP-activated protein kinase (AMPK) and sirtuin1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator 1-alpha pathways."
- "Disruption of this ESCRT-autophagy interface has emerged as a common pathological feature across major neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis/frontotemporal dementia."
- "Therapeutic neutralization of IL17A with a monoclonal antibody (IL17A mAb) ameliorates disease phenotypes in R6/2 HD mice, improving motor performance, extending survival, and reducing gliosis."
- "HCQ exerts multiple beneficial cardiovascular effects through anti-inflammatory, antithrombotic, metabolic, and endothelial-protective mechanisms."
- "Mechanistically, we identified a protective signaling axis involving p38 MAPK, MK2, and HSP27 that senses ANXA11-induced lysosomal damage and initiates lysophagy."
- "TDP-43 mislocalization, post-translational modifications, and aggregation potentiate neuronal loss through disruption of RNA metabolism, nucleocytoplasmic transport, and protein homeostasis."
- "The progressive collapse of these adaptive mechanisms may contribute to chondrocyte degeneration and to the pathogenesis of cartilage damage in AKU."
- "Functionally, LAMP3 overexpression alleviated NaIO3-induced LMP, improved lysosomal function, and alleviated autophagic impairment."
- "Levacetylleucine rapidly alters TFEB translocation between the cytoplasm and the nucleus in a biphasic, homeostasis-restoring manner."
- "Unexpectedly, these structures are found to control cytoplasmic signaling through FAM134B/C-mediated lysosomal sequestration of RhoA."
- "BCL2-associated athanogene 3 (BAG3) protein has a role in initiating the ALP."
- "Expression of BAG3V468M induces a DCM-like phenotype in vivo associated with disrupted myocardial architecture and altered proteostasis."
- "All bvFTD iMG had fewer LAMP2-A-positive vesicles compared to control iMG."
- "LAPTM4A (lysosome-associated protein transmembrane 4 alpha) stood out as a significant protective lysosome-localized protein from the screening."
- "These findings highlight the potential of LysoDots as a biocompatible, photostable, multi-functional nanomaterial for long-term monitoring of lysosomal dynamics and cellular homeostasis."
- "IL17A mAb also attenuates mHTT aggregation and enhances neuroprotective signaling, as evidenced by increased expression of DLG4/PSD-95, phosphorylated CREB1, and BDNF."
- "The 'protein-as-pathogen' model, where shed viral proteins act as soluble neurotoxins, is now central to understanding this phenomenon."
- "In addition, the potentials of fluid biomarkers, including cerebrospinal fluid poly (GP) and blood neurofilament light chain (NfL), for diagnosis, disease monitoring, and therapeutic assessment were shown."
- "Under basal conditions, NMR skin fibroblasts exhibit a greater abundance of LC3-positive structures than HeLa cells, together with a mixed population of autophagosomes and autolysosomes, indicating a distinct steady-state organisation of the ALP."
- "In addition, the LC-II/I ratio increased, indicating increased autophagic flux."
- "Mechanistically, GCGR loss disrupts its association with the V-ATPase V1A subunit ATP6V1A, compromises V1-V0 assembly, and thereby impairs lysosomal acidification."
- "Moreover, treatment with the V-ATPase inhibitor BafA1 aggregated cellular senescence phenotype and autophagy inhibition and this phenomenon partially reversed by ATP6V1A overexpression."
- "We find that engraftment of wild-type, but not Grn-deficient, human microglia restore brain-wide progranulin levels, normalize microglial transcriptional states, and ameliorate pathological, functional, and behavioral phenotypes associated with progranulin loss."
- "Neuroprotective effects of such substances as spermidine, urolithin A, resveratrol, αlipoic acid, MitoQ, SkQ1, or CoQ10 have been shown using preclinical research."
- "Importantly, this review highlights a stage- and context-dependent paradox in which the same galectin axis can amplify neuroinflammation and proteopathic spread in some settings yet support recovery or tissue protection in others."
- "By relating neighborhood-level depletion in disease to gene expression in controls, we found that baseline cellular respiration and ATP synthesis predict neuronal vulnerability in disease."
- "Together, these data provide novel insight into TE transcript dynamics in microglia, highlighting TE transcript patterns that differ from those observed in whole-brain samples and other cell types in aging and AD."
- "C9ORF72 LOF disrupted lysosomal and autophagic pathways in microglia, impairing the immune homeostasis."