Of interest, new detailed study on TDP-43 accumulation and the role of autophagy :

Ageing Res Rev. 2024 Jul 27:100:102441. doi: 10.1016/j.arr.2024.102441.

TDP-43 proteinopathy in frontotemporal lobar degeneration and amyotrophic lateral sclerosis: From pathomechanisms to therapeutic strategies

"Accumulation of TDP-43 aggregates in the central nervous system is a hallmark of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Autophagy, a major and highly conserved degradation pathway, holds the potential for degrading aggregated TDP-43 and alleviating FTLD/ALS".



"Crucially, the harmful impacts of misfolded, unfolded, or aggregated TDP-43 can be mitigated by enhancing or restoring protein quality control mechanisms. Thus, comprehending how these clearance pathways facilitate the breakdown of misfolded, unfolded, or aggregated TDP-43, and potentially manipulating them, could be beneficial for enhancing neuronal viability and mitigating neurodegeneration."




" Despite increased interest in autophagy activation as a potential therapeutic strategy for promoting clearance of protein aggregates and neuropotection, treatments targeting autophagy should be carefully evaluated as overactivation of autophagy accelerates the progression of neurodegenerative diseases. In addition, the development or establishment of a drug delivery system across the blood-brain barrier that targets the central nervous system may allow lower effective drug doses for treatment. Future studies should focus on developing therapeutic interventions that precisely restore the function of protein clearance systems in FTLD and ALS."