PathMap Literature Based Discovery Engine

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Experiment #00000139

Foundational Dietary Theory: The dietary synergy between Hi-Maize and 6x Spermidine Yeast creates a potential cellular supply-and-clearance loop within the brain's astrocytes. Circulating spermidine metabolites utilize documented astrocytic polyamine uptake systems to access the central nervous system. Once inside, this exogenous spermidine drives FAM134B-mediated ER-phagy, clearing the endoplasmic reticulum matrix. This clearance removes the ER-stress bottleneck, allowing newly transcribed astrocytic EAAT2—upregulated by gut-derived butyrate from Hi-Maize fermentation—to successfully traffic to the plasma membrane and mitigate synaptic glutamate excitotoxicity.

Starch, Resistant _gates_from_starch__resistant Butyric Acid _gates_to_butyric_acid _gates_from_butyric_acid Glutamate Plasma Membrane Transport Proteins _gates_to_glutamate_plasma_membrane_transport_proteins Spermidine _gates_from_spermidine Autophagy
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Experiment #00000138

Dietary butyrate from resistant starch may synergize with sulforaphane-driven Nrf2 activation and spermidine-mediated FAM134B ER-phagy in order to restore astrocytic EAAT2 membrane trafficking and potentially clear synaptic glutamate excitotoxicity in neurodegeneration. (Literature Based Discovery)

Starch, Resistant _gates_from_starch__resistant Butyrate _gates_to_butyrate _gates_from_butyrate NF-E2-Related Factor 2 _gates_to_nf_e2_related_factor_2 Sulforaphane _gates_from_sulforaphane Spermidine
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Experiment #00000130

Targeted alteration of the oral microbiome via a single polyphenol- and fiber-dense meal plan creates an immediate shift in the microbial composition of involuntary nocturnal microaspiration droplets. Upon entry into the lower respiratory tract, this eubiotic bacterial influx acts as an acute molecular signal that rapidly modulates microglia reactivity and neuroinflammation via the lung-brain axis, bypassing systemic colonic metabolite transport.

Dietary modification _gates_from_dietary_modification Dysbiosis _gates_to_dysbiosis _gates_from_dysbiosis Respiratory Aspiration _gates_to_respiratory_aspiration _gates_from_respiratory_aspiration Microglia _gates_to_microglia
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Experiment #00000126

Hypothesis: Intranasal delivery of Spermidine-modified Ginseng Extracellular Vesicles (S-GEVs) loaded with multi-targeted mRNA suppresses MARK2-eIF2α-driven RAN translation to prevent dipeptide repeat clogging of FG-nucleoporins, synergizing with progranulin-mediated lysosomal clearance to arrest TMEM106B amyloid accumulation and block the execution of p38-Lamin B1-dependent Karyoptosis in motor neurons.

Spermidine _gates_from_spermidine Lysosomal Degradation _gates_to_lysosomal_degradation _gates_from_lysosomal_degradation Protein Aggregates _gates_to_protein_aggregates _gates_from_protein_aggregates Cell Death _gates_to_cell_death
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Experiment #00000101

Hypothesis: If Botox were injected into the nerve ending on the third toe on the left foot, the toxin can "climb" retrograde from toe through motor neurons eventually to the brain and temporarily inhibit vesicular docking "from toe to head", potentially allowing a timed pharmacological therapeutic window for toxic EV clearance through the lymph system instead of docking and seeding.

Botulinum Toxins, Type A _gates_from_botulinum_toxins__type_a Axonal Transport _gates_to_axonal_transport _gates_from_axonal_transport SNARE Proteins _gates_to_snare_proteins _gates_from_snare_proteins Lymphatic Vessel Endothelial Hyaluronan Receptor-1 _gates_to_lymphatic_vessel_endothelial_hyaluronan_receptor_1
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Experiment #00000092

A Top-Down Mechanism for Sporadic ALS Initiated by Ocular Metal Dyshomeostasis and Retrograde Exosomal Transport along the Subcortical Visual Axis

Eye Diseases _gates_from_eye_diseases Retinal Diseases _gates_to_retinal_diseases _gates_from_retinal_diseases Extracellular Vesicles _gates_to_extracellular_vesicles _gates_from_extracellular_vesicles Motor Neurons _gates_to_motor_neurons
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Experiment #00000086

Parkinson's Disease versus Alzheimer's Disease: Shared and Exclusive Pathways

Pathologic Processes _gates_from_pathologic_processes Mitochondrial Diseases _gates_to_mitochondrial_diseases Lipid Metabolism Disorders _gates_from_lipid_metabolism_disorders Lipid Droplet Accumulation _gates_to_lipid_droplet_accumulation _gates_from_lipid_droplet_accumulation Lysosomal Storage Diseases
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Experiment #00000068

ALS; FUS; STMN2; TDP-43; protein translation; stress granule

Cell Nucleus _gates_from_cell_nucleus RNA Splicing _gates_to_rna_splicing _gates_from_rna_splicing Protein Biosynthesis _gates_to_protein_biosynthesis _gates_from_protein_biosynthesis Motor Neuron Disease _gates_to_motor_neuron_disease
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Experiment #00000065

Does pathologically seeded TDP-43 exit the retina via anterograde axonal transport along the optic tract to midbrain hubs, enter the systemic circulation inside extracellular vesicles, and subsequently traffic into pancreatic beta-cells to accelerate type 2 diabetes phenotypes?

TAR DNA-Binding Protein 43 _gates_from_tar_dna_binding_protein_43 Extracellular Vesicles _gates_to_extracellular_vesicles Systemic circulating EVs _gates_from_systemic_circulating_evs Insulin-Secreting Cells _gates_to_insulin_secreting_cells Axonal Transport _gates_to_axonal_transport
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Experiment #00000039

What is the current evidence for RGNEF (ARHGEF28) functioning as a primary upstream regulator of axonal transport and TDP-43 homeostasis in ALS, and how does the failure of this 'terminal tether' initiate the pathological continuum compared to downstream protein aggregation?

Metabolic Stress _gates_from_metabolic_stress Protein Aggregation _gates_to_protein_aggregation _gates_from_protein_aggregation RNA Metabolism _gates_to_rna_metabolism _gates_from_rna_metabolism Axonal Transport _gates_to_axonal_transport
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Experiment #00000038

Map the direct mechanical and axonal transport pathways connecting intranasal administration or trigeminal nerve delivery to the clearance of TDP-43 aggregates in sporadic ALS, and the delivery of CRISPR-Cas/ASO gene therapies targeting C9orf72 hexanucleotide repeat expansions in the cerebellum and brainstem.

Intranasal Route _gates_from_intranasal_route Blood-Brain Barrier _gates_to_blood_brain_barrier C9orf72 Protein _gates_to_c9orf72_protein _gates_from_c9orf72_protein Brain _gates_to_brain Intranasal Administration
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Experiment #00000016

Analyze the potential for zinc-binding competition between synaptic transporters (e.g., SLC39A8, ZnT3) and ALS-associated proteins (RGNEF, TDP-43) in the RGC-thalamic axis. Can this competition explain the coexistence of RGC excitotoxicity and STMN2 depletion in clinical samples?

TAR DNA-Binding Protein 43 _gates_from_tar_dna_binding_protein_43 Stathmin 2 _gates_to_stathmin_2 SLC39A8 protein, human _gates_from_slc39a8_protein__human Zinc _gates_to_zinc Excitotoxicity _gates_from_excitotoxicity
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Experiment #00000007

Simply put, we still don’t know why neurons are dying in ALS, and why motor neurons die while other types of neurons don’t. Even for genetic forms c9orf72 familial ALS, why is it that the mutation is in every cell but the motor neurons are dying ie have increased susceptibility?

Axonal Transport _gates_from_axonal_transport Motor Neuron Disease _gates_to_motor_neuron_disease C9orf72 Repeat Expansion _gates_from_c9orf72_repeat_expansion Dipeptide Repeats _gates_to_dipeptide_repeats _gates_from_dipeptide_repeats VAPB protein, human
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