TDP-43 pathology is linked to motor neuron loss but is independent of stress granules in vivo - PubMed
5 hours ago
- #stress granules
- #TDP-43
- #neurodegenerative diseases
- TDP-43 pathology is linked to motor neuron loss but is independent of stress granules in vivo.
- Nuclear depletion and cytoplasmic aggregation of TDP-43 are hallmarks of neurodegenerative diseases like ALS, FTD, Alzheimer's, and LATE.
- Chronic ISR activation and stress granules were hypothesized to initiate TDP-43 inclusions, but clinical trials targeting these failed.
- A hyperthermia paradigm shows stress granule-associated proteins persist as reversible structures distinct from TDP-43 puncta.
- Mutant TDP-43 mice with impaired stress granule response show TDP-43 nuclear export and cytoplasmic accumulation under stress.
- Recurrent stress in these mice leads to selective loss of spinal α-motor neurons.
- Findings challenge prevailing models of TDP-43 pathogenesis and question therapeutic strategies targeting the ISR.