Mechanisms to regulate soluble TDP43
TDP43 mislocalization and dysfunction are characteristic of ALS, FTLD, and related neurodegenerative diseases.
The researchers uncover pre- and posttranslational mechanisms responsible for regulating cytoplasmic, aggregation prone shortened (s)TDP43 isoforms.
The authors demonstrate that sTDP43 is created as a by-product of TDP43 autoregulation and cleared by nonsense-mediated RNA decay (NMD). sTDP43-encoding transcripts that escape NMD are rapidly degraded post-translationally via the proteasome and macroautophagy. sTDP43 inhibits full-length TDP43, providing key insights into native pathways for maintaining TDP43 homeostasis.
Overexpressing sTDP43 results in neurodegeneration via N-terminal oligomerization and impairment of flTDP43 splicing activity, in addition to RNA-binding-dependent gain-of-function toxicity.
https://www.cell.com/cell-reports/fulltext/S2211-1247(24)01464-5
