Silencing either TDP-43 or FUS/TLS reduces HDAC6 mRNA levels, indicating a crucial link between these RNA-binding proteins and HDAC6 (44).
[Note from the third reference]we are the first to confirm that HDAC6-dependent aggresome formation is partially involved in skein-like TDP-43 inclusion of sporadic ALS.
[Note from the forth reference]In this study, we found that HDAC6 overexpression decreased the levels of insoluble and cytosolic TDP-43 protein in TDP-43-overexpressing N2a cells. In addition, TDP-43 overexpression upregulated HDAC6 protein and mRNA levels, and knockdown of Hdac6 elevated the total protein level of TDP-43. We further found that HDAC6 modulates TDP-43-induced UPS impairment via the autophagy-lysosome pathway (ALP). We also showed that TDP-43 promoted a short lifespan in flies and that the accumulation of ubiquitin aggregates and climbing defects were significantly rescued by overexpression of HDAC6 in flies. Taken together, these findings suggest that HDAC6 overexpression can mitigate neuronal toxicity caused by TDP-43-induced UPS impairment, which may represent a novel therapeutic approach for ALS.
In addition, TDP-43 overexpression upregulated HDAC6 protein and mRNA levels, and knockdown of Hdac6 elevated the total protein level of TDP-43.
[note from the fifth reference]:
our findings demonstrated that depletion of TDP-43 may protect RGC-5 cells against oxidative stress-mediated apoptosis and autophagy by suppressing its target HDAC6. Thus, the TDP-43/HDAC6 axis might be a promising strategy for the treatment of DR.
Note: TDP-43 is an alias for TARDBP.