HDAC6 and TDP-43 promote autophagy impairment in amyotrophic lateral sclerosis

TDP-43 is known to bind the mRNA of histone deacetylase 6 (HDAC6), influencing its RNA translation. Many studies suggest that HDAC6 participates in the regulation of autophagy, which we found impaired in sporadic amyotrophic lateral sclerosis (sALS) patients. Aim of this work is to evaluate the interaction between TDP-43 and HDAC6 mRNA and to evaluate the effect of the up- and down-regulation of HDAC6 on autophagy in SH-SY5Y cells. Protein level of HDAC6 and TDP-43 binding with HDAC6 mRNA by RNA immunoprecipitation were studied on sALS peripheral blood mononuclear cells (PBMCs). Initially, we observed increased level of HDAC6 protein and increased binding of its mRNA with TDP-43 in sALS PBMCs. We observed that TDP-43 transfection and aggregation in SH-SY5Y cells leads to overexpression of HDAC6. Our results indicate that the autophagy pathway is sensitive to both extremes of alpha-tubulin acetylation. Indeed, a marked reduction due to HDAC6 overexpression, as well as an excessive increase following HDAC6 downregulation, both result in autophagic dysfunction. This work supports the hypothesis that dysregulation of HDAC6 is a key factor in the disruption of the autophagy pathway previously detected in sALS PBMCs. Our work suggests for the first time that TDP-43 influences autophagy by binding and modulating HDAC6 mRNA. This new pathway suggests that in ALS the aggregation of TDP-43 leads to the overexpression of HDAC6 which impairs autophagy. Thus, our work suggest that in sALS HDAC6 should be tuned and these findings could be exploited in the future as possible therapeutic target.