期刊
NEURODEGENERATIVE DISEASES
卷 15, 期 6, 页码 339-349出版社
KARGER
DOI: 10.1159/000437208
关键词
Annyotrophic lateral sclerosis; SOD1 mutant; HDAC6; Aggresome; Aggregates; Autophagy; Lysosonne
资金
- Chungnam National University (NRF of Korea) [2012M3A9C6050087]
- NIH [R01NS077284, 2R01-NS054022, AR055613]
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [R01AR055613] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS077284, R01NS054022] Funding Source: NIH RePORTER
Aberrant accumulation of protein aggregates is a pathological hallmark of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Although a buildup of protein aggregates frequently leads to cell death, whether it is the key pathogenic factor in driving neurodegenerative disease remains controversial. HDAC6, a cytosolic ubiquitin-binding deacetylase, has emerged as an important regulator of ubiquitin-dependent quality control autophagy, a lysosome-dependent degradative system responsible for the disposal of misfolded protein aggregates and damaged organelles. Here, we show that in cell models HDAC6 plays a protective role against multiple disease-associated and aggregation-prone cytosolic proteins by facilitating their degradation. We further show that HDAC6 is required for efficient localization of lysosomes to protein aggregates, indicating that lysosome targeting to autophagic substrates is regulated. Supporting a critical role of HDAC6 in protein aggregate disposal in vivo, genetic ablation of HDAC6 in a transgenic SOD1(G93A) mouse, a model of ALS, leads to dramatic accumulation of ubiquitinated SOD1G93A protein aggregates. Surprisingly, despite a robust buildup of SOD1(G93A) aggregates, deletion of HDAC6 only moderately modified the motor phenotypes. These findings indicate that SOD1(G93A) aggregation is not the only determining factor to drive neurodegeneration in ALS, and that HDAC6 likely modulates neurodegeneration through additional mechanisms beyond protein aggregate clearance. (C) 2015 S. Karger AG, Basel
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