The Role of HDAC6 in TDP-43-Induced Neurotoxicity and UPS Impairment.

Shinrye Lee,Mookyung Cheon,Younghwi Kwon,Seongsoo Lee,Yu-Mi Jeon,Kiyoung Kim,Hyung-Jun Kim,Sang Ryong Kim,Seyeon Kim,Myungjin Jo

doi:10.3389/fcell.2020.581942

Abstract

Transactive response DNA-binding protein 43 (TDP-43)-induced neurotoxicity is currently well recognized as a contributor to the pathology of amyotrophic lateral sclerosis (ALS), and the deposition of TDP-43 has been linked to other neurodegenerative diseases, such as frontotemporal lobar degeneration (FTLD) and Alzheimer’s disease (AD). Recent studies also suggest that TDP-43-induced neurotoxicity is associated with ubiquitin-proteasome system (UPS) impairment. Histone deacetylase 6 (HDAC6) is a well-known cytosolic deacetylase enzyme that suppresses the toxicity of UPS impairment. However, the role of HDAC6 in TDP-43-induced neurodegeneration is largely unknown. 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.

Highlights

Transactive response DNA-binding protein 43 (TDP-43) is an evolutionarily conserved member of the heterogeneous nuclear ribonucleoprotein family, and it is encoded by the TARDBP gene (Ou et al, 1995)
We found that Histone deacetylase 6 (HDAC6) overexpression clearly reduced total TDP-43-GFP protein levels compared to those of the control (Figure 1C)
We observed that HDAC6 overexpression significantly decreases the protein level of disease-associated TDP-43 mutant (TDP-43Q331K-GFP) (Supplementary Figure S1)

Summary

Introduction

Transactive response DNA-binding protein 43 (TDP-43) is an evolutionarily conserved member of the heterogeneous nuclear ribonucleoprotein (hnRNP) family, and it is encoded by the TARDBP gene (Ou et al, 1995). It is already known that cytoplasmic accumulation of TDP43 aggregates is one of the major characteristics of TDP43 proteinopathy (Kim et al, 2014; Scotter et al, 2015; Shenouda et al, 2018), and this is a common pathological feature associated with many neurodegenerative diseases, such as Alzheimer’s disease (AD), frontotemporal lobar degeneration (FTLD), and amyotrophic lateral sclerosis (ALS) (Neumann et al, 2006; Mackenzie et al, 2011; Tremblay et al, 2011) Many neuropathological mechanisms, such as oxidative stress, mitochondrial dysfunction, neuroinflammation, and ER stress, are linked to TDP-43 proteinopathy (Duan et al, 2010; Kim et al, 2014; Zhao et al, 2015; Wang et al, 2019). Emerging clinical and experimental evidence suggests that dysfunctions in protein quality control, including problems with the ubiquitinproteasome system (UPS) impairment, are the core pathological mechanism of TDP-43-mediated neurodegeneration (Scotter et al, 2014; Lee et al, 2019)

Methods

Results

Discussion

Conclusion