TDP-43 Pathology Disrupts the HGS-PYGB Autophagy Receptor Cascade in Motor Neur…

Proposed by etl-backfill

TARDBP (TDP-43), HGS, PYGB neurodegeneration market 79% proposed
Compare across mechanisms →
Composite
70%
Novelty
70%
Feasibility
65%
Impact
75%
Mechanistic
75%
Druggability
55%
Safety
65%
Confidence
72%

Mechanistic description

TDP-43 aggregates sequester hepatocyte growth factor-regulated tyrosine kinase substrate (HGS), a critical hub coordinating early endosome-to-autophagosome cargo delivery. In motor neurons where TDP-43 nuclear loss and cytoplasmic aggregation occurs early in ALS, HGS is functionally depleted, creating specific vulnerability where upstream autophagy induction cannot compensate for downstream cargo recognition failure. This hypothesis survived critique due to its mechanistic specificity for motor neurons and direct connection to the hallmark pathology of >95% of ALS cases.

Mechanism / pathway

  1. TARDBP (TDP-43), HGS, PYGB
  2. neurodegeneration

Evidence for (4)

  • TDP-43 pathology is a hallmark of >95% of ALS cases

    PMID:19023281

  • HGS is an ALS-risk gene and interacts with autophagy machinery

    PMID:29507358

  • HGS knockdown specifically impairs autophagy in neurons but not other cell types

    PMID:28760759

  • TDP-43 binds 3' UTR regions of multiple autophagy genes

    PMID:29417807

Evidence against (1)

Evidence matrix

4 supporting 0 contradicting
100% supporting

Supporting

  • TDP-43 pathology is a hallmark of >95% of ALS cases PMID:19023281
  • HGS is an ALS-risk gene and interacts with autophagy machinery PMID:29507358
  • HGS knockdown specifically impairs autophagy in neurons but not other cell types PMID:28760759
  • TDP-43 binds 3' UTR regions of multiple autophagy genes PMID:29417807

Contradicting

No contradicting evidence recorded.

Cite this hypothesis

Cite this hypothesis
Citation

etl-backfill (2026). TDP-43 Pathology Disrupts the HGS-PYGB Autophagy Receptor Cascade in Motor Neur…. SciDEX hypothesis. https://prism.scidex.ai/hypotheses/h-183fff58

BibTeX 
@misc{scidex_hypothesis_h183fff5,
  title        = {TDP-43 Pathology Disrupts the HGS-PYGB Autophagy Receptor Cascade in Motor Neur…},
  author       = {etl-backfill},
  year         = {2026},
  howpublished = {SciDEX hypothesis},
  url          = {https://prism.scidex.ai/hypotheses/h-183fff58},
  note         = {SciDEX artifact hypothesis:h-183fff58}
}

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