Mechanistic description
Shared mechanism across ALS, FTD, PD: TBK1 coordinates selective autophagy adaptors and innate immune tone. TBK1 haploinsufficiency causes ALS/FTD, while the same PINK1/Parkin/TBK1-adjacent mitochondrial quality-control network constrains PD-like mitochondrial and alpha-synuclein stress.
Falsifiable prediction: Partial TBK1 restoration should increase phospho-OPTN recruitment and reduce p62/TDP-43 aggregate load in ALS/FTD neurons; in PD dopaminergic neurons it should improve damaged-mitochondria clearance after rotenone by at least 20%.
Proposed experiment: Use TBK1 haploinsufficient ALS/FTD neurons and PD dopaminergic stress models; compare TBK1 rescue, kinase-dead TBK1, and vector controls; measure p-OPTN, p62, mitophagy flux, interferon/NF-kB markers, aggregate burden, and survival.
Cross-disease confidence rationale: Strong ALS/FTD genetics, with PD extrapolation through selective mitophagy network biology.
Internal SciDEX support: SciDEX support query found 29 matching hypotheses across 8 disease labels, including 29 with debate_count > 0.
Generated by task ffd81f3a-7f04-4db1-8547-1778ce030e89 as a cross-disease mechanism synthesis, not a single-disease hypothesis renamed as multi-disease.
Mechanism / pathway
- TBK1
- TBK1, OPTN, p62/SQSTM1 selective autophagy and innate immune signaling
- multi
Evidence for (3)
TBK1 haploinsufficiency causes familial ALS and FTD.
PINK1/PARKIN signaling connects mitochondrial quality control and neuroinflammation.
PINK1/Parkin mitochondrial fidelity is central in PD.
Evidence against (1)
Evidence matrix
Supporting
- TBK1 haploinsufficiency causes familial ALS and FTD. PMID:25803835 · 2015 · 10.1038/nn.4000
- PINK1/PARKIN signaling connects mitochondrial quality control and neuroinflammation. PMID:33168089 · 2020 · 10.1186/s40478-020-01062-w
- PINK1/Parkin mitochondrial fidelity is central in PD. PMID:25611507 · 2015 · 10.1016/j.neuron.2014.12.007
Contradicting
No contradicting evidence recorded.
Top-ranked evidence
trust_score × relevance_score × exp(-recency_weight × recency_days / 365)
Supports · top 3
- #1 609cb8c5-644d-4bf2-816b-63fdb0513d7c 0.470
- #2 paper-d9ef694990e7 0.470
- #3 paper-cd0a397533a5 0.235
Cite this hypothesis
Cite this hypothesis
etl-backfill (2026). TBK1-OPTN-p62 selective autophagy failure across ALS, FTD, and PD-like proteoto…. SciDEX hypothesis. https://prism.scidex.ai/hypotheses/h-cross-synth-tbk1-optn-autophagy
@misc{scidex_hypothesis_hcrosssy,
title = {TBK1-OPTN-p62 selective autophagy failure across ALS, FTD, and PD-like proteoto…},
author = {etl-backfill},
year = {2026},
howpublished = {SciDEX hypothesis},
url = {https://prism.scidex.ai/hypotheses/h-cross-synth-tbk1-optn-autophagy},
note = {SciDEX artifact hypothesis:h-cross-synth-tbk1-optn-autophagy}
}