title: Uncoupling of Protein Aggregation and Neurodegeneration in a Mouse Amyotrophic Lateral Sclerosis Model.
abstract: 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 SOD1G93A mouse, a model of ALS, leads to dramatic accumulation of ubiquitinated SOD1G93A protein aggregates. Surprisingly, despite a robust buildup of SOD1G93A aggregates, deletion of HDAC6 only moderately modified the motor phenotypes. These findings indicate that SOD1G93A 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.
authors.affiliation: Graduate School of Analytical Science and Technology (GRAST), Chungnam National University, Daejeon, Republic of Korea.
authors.forename: Joo-Yong
authors.initials: JY
authors.lastname: Lee
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Kawaguchi
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.forename: Meghan
authors.initials: M
authors.lastname: Kapur
authors.forename: Su Jin
authors.initials: SJ
authors.lastname: Choi
authors.forename: Hak-June
authors.initials: HJ
authors.lastname: Kim
authors.forename: Song-Yi
authors.initials: SY
authors.lastname: Park
authors.forename: Haining
authors.initials: H
authors.lastname: Zhu
authors.forename: Tso-Pang
authors.initials: TP
authors.lastname: Yao
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000235:genetics; D004195:Disease Models, Animal; D006655:Histone Deacetylases / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D008822:Mice, Transgenic; D066263:Protein Aggregation, Pathological / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D025801:Ubiquitin; D006655:Histone Deacetylases