Hypothesis corpus
Scored, debated, and tradable. Each hypothesis carries composite, novelty, impact, mechanistic, druggability, and safety scores — plus a live market price when a collider is open.
Showing als hypotheses, sorted by Composite score.
TBK1 Loss Triggers Astrocyte-to-Neuron Senescence Propagation Through SASP-Mediated Paracrine Signaling in ALS
TBK1 → NF-κB / IRF3 / p62-autophagy / SASP effectors alsMicroglia-specific TBK1 loss produces an aged-like, pro-inflammatory signature in an ALS/FTD mouse model.
h-var-1f97821344eIF2α Phosphorylation Imbalance Disrupts Mitochondrial Protein Import and Bioenergetics in ALS Motor Neurons
EIF2S1,eIF2α,PERK,GCN2,ATF4,TOMM20,TIMM23,NDUFS1,NDUFS3,COX4I1,COX5A,mitochondrial protein import als58% posterior · 1 signalRepeat-associated non-AUG translation in C9orf72-ALS/FTD is driven by neuronal excitation.
h-var-501d347dbbTBK1 Loss Triggers eIF2α-Mediated Translational Repression Through Microglial SASP-Induced Integrated Stress Response in Motor Neurons
TBK1, EIF2S1 alsMicroglia-specific TBK1 loss produces an aged-like, pro-inflammatory signature in an ALS/FTD mouse model.
h-var-a7e2e13fafeIF2α Phosphorylation Imbalance Creates Integrated Stress Response Overflow That Represses Axonal Protein Synthesis in ALS
EIF2S1,eIF2α,PERK,GCN2,ATF4,ATF5,CHOP,DDIT3,integrated stress response,protein synthesis als 90%66% posterior · 8 signalsRepeat-associated non-AUG translation in C9orf72-ALS/FTD is driven by neuronal excitation.
h-alsmnd-870c6115d68cTBK1 Loss Locks Microglia in an Aged/Senescent Transcriptional State, Fueling ALS-Associated SASP
TBK1 → NF-κB / IRF3 / p62-autophagy / cGAS-STING axis als 88%72% posterior · 10 signalsMicroglia-specific TBK1 loss produces an aged-like, pro-inflammatory signature in an ALS/FTD mouse model.
h-31ca9240f9fcRBM45 Liquid-Liquid Phase Separation Dominance Hijacks RNA Processing Condensates Toward Pathological Aggregation in ALS
RBM45,GSK3B,TDP-43,TARDBP,hnRNP A1,HNRNPA1,phase separation,Liquid droplet als 87%50% posterior · 12 signalsFamily-based exome sequencing identifies RBM45 as a possible candidate gene for frontotemporal dementia and amyotrophic lateral sclerosis.
h-alsmnd-9d62ae58bdc1SFPQ Paralog Displacement Triggers Cryptic Polyadenylation and Global RNA Stability Loss in ALS Motor Neurons
SFPQ,NONO,PSP1,TARDBP,poly(A) machinery,CPSF,PABPN1 als 86%83% posterior · 14 signalsTDP-43 nuclear loss in FTD/ALS causes widespread alternative polyadenylation changes.
h-alsmnd-c5d2e9c2edebhnRNP A2/B1 Staufen2-Mediated Axonal RNA Granule Transport Failure Drives Distal Axon Degeneration in ALS
HNRNPA2B1,STAU2,PRMT1,GSK3B,MAP1B,β-actin,axonal transport machinery als 85%Altered mRNA transport and local translation in i3Neurons with RNA-binding protein knockdown.
h-alsmnd-006d646506abATM Kinase Hyperactivation Triggers DNA Damage Response Overflow and p53-Dependent Motor Neuron Apoptosis in ALS
ATM,CHEK2,TP53,BAX,PUMA,BCL2,DNA damage response,oxidative stress als 84%The DNA damage response (DDR) is induced by the C9orf72 repeat expansion in amyotrophic lateral sclerosis.
h-alsmnd-9d07702213f0GLE1-Mediated mRNA Export Defect Creates Translation-Competent mRNA Starvation in ALS Motor Neuron Axons
GLE1,DBP10,EXPORTIN-1,XPO1,mRNA export machinery,NPC als 82%Deficiency in the mRNA export mediator Gle1 impairs Schwann cell development in the zebrafish.
h-alsmnd-e448328ae294TIA1 Low-Complexity Domain Oxidation Drives Aberrant Stress Granule Assembly and TDP-43 Mislocalization in ALS Motor Neurons
TIA1,TDP-43,TARDBP,G3BP1,MAPK1,Oxidative stress response als 81%Amyotrophic lateral sclerosis (ALS) linked mutation in Ubiquilin 2 affects stress granule dynamics.
h-alsmnd-54f981ca6a25MATR3 Nuclear Body Disruption Impairs RNA Processing Hubs and Triggers Splicing Defects in ALS Motor Neurons
MATR3,U1 snRNP,SNRPB,SNRNP70, splicing machinery,spliceosome als 80%Amyotrophic Lateral Sclerosis Overview.
h-alsmnd-01446b71d93fSTMN2 Cryptic Exon Inclusion is the Earliest Loss-of-Function Marker of TDP-43 Nuclear Depletion in ALS Motor Neurons
TARDBP als 76%[Amyotrophic lateral sclerosis (ALS) - diagnosis, course of disease and treatment options].
ec8b839c-6440-45dc-aff6-5edea1fd2d6dSASP-Secreted MMP-9 from Senescent Microglia Generates Pathological TDP-43 C-Terminal Fragments That Propagate ALS Pathology
MMP9 → TARDBP (C-terminal fragments) → cytoplasmic aggregation seeding als 72%53% posterior · 1 signalReactive microglia expressing MMP-9 remodel perineuronal nets around motor neurons in a TDP-43 ALS mouse model.
h-530326b97069EZH2-Mediated H3K27me3 Spreading in Senescent ALS Microglia Silences Neuroprotective Gene Programs — Reversible by EZH2 Inhibitors
EZH2 (PRC2) → H3K27me3 silencing of BDNF, GRN, TREM2, MerTK als 71%EZH2 rises in activated microglia after ischemic injury, and DZNep suppresses the microglial inflammatory program.
h-f373e16bb108CCL2-CCR2 Driven Macrophage Infiltration Selectively Strips Fast-Fatigable NMJs via MMP-9 in ALS
CCL2 als 68%MCP1-CCR2 and neuroinflammation in the ALS motor cortex with TDP-43 pathology.
44b404ab-eabb-45a2-ab3a-9e2f3ecf3b7bArginine Methylation Loss on FUS RGG Domains Drives Irreversible Phase Transition to Amyloid in ALS
FUS als 68%ALS-FUS mutations cause abnormal PARylation and histone H1.2 interaction, leading to pathological changes.
897f3e4a-f96a-4a65-b3c8-61e20a1054daClosed-loop optogenetic targeting of PV interneurons to restore motor circuit inhibition and attenuate excitotoxicity-driven motor neuron degeneration in ALS
als 63%Pathophysiology and Diagnosis of ALS: Insights from Advances in Neurophysiological Techniques.
h-analogy-38e863caClosed-loop transcranial focused ultrasound targeting motor cortex SST interneurons to restore cortical oscillations via corticospinal excitability gating in ALS
SST als 63%MRI-Targeted or Standard Biopsy for Prostate-Cancer Diagnosis.
h-analogy-410d3197Gamma entrainment therapy to restore motor cortical inhibitory-excitatory balance in ALS
PVALB als 63%Inhibition of GABA interneurons in the mPFC is sufficient and necessary for rapid antidepressant responses.
h-analogy-e866a41fTBK1 Loss Drives Motor Neuron Death Through Impaired Mitophagy and Metabolic Collapse
TBK1 → OPTN / p62 / FIP200 / mitophagy machinery als 53%Microglia-specific TBK1 loss produces an aged-like, pro-inflammatory signature in an ALS/FTD mouse model.
h-var-b7e8e12838SASP-Secreted MMP-9 from Senescent Microglia Disrupts TDP-43 Nuclear Retention Leading to Cytoplasmic Mislocalization in ALS
MMP9 → nuclear import machinery (KPNA1, NUP proteins, LMNA) → TARDBP cytoplasmic mislocalization als 51%47% posterior · 1 signalReactive microglia expressing MMP-9 remodel perineuronal nets around motor neurons in a TDP-43 ALS mouse model.
h-var-a3cfa5bb63Disease-Elevated CHI3L1/CHIT1 Chitinases Are Biomarkers and Partial Compensators for Senescent Microglial Phagocytic Failure
CHI3L1 (YKL-40), CHIT1, CHI3L2 / MMP-2 / TREM2 / MerTK als 50%CSF CHIT1, CHI3L1, and CHI3L2 are elevated in ALS and track with neuroinflammatory disease state.
h-177d9cb05108TBK1 Loss Drives Microglial Senescence-SASP to Generate MMP-9-Mediated TDP-43 C-Terminal Fragments in ALS
TBK1 als 50%47% posterior · 1 signalMicroglia-specific TBK1 loss produces an aged-like, pro-inflammatory signature in an ALS/FTD mouse model.
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