Uncoupling of Protein Aggregation and Neurodegeneration in a Mouse Amyotrophic Lateral Sclerosis Model

Joo Yong Lee, Yoshiharu Kawaguchi, Ming Li, Meghan Kapur, Su Jin Choi, Hak June Kim, Song Yi Park, Haining Zhu, Tso Pang Yao

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

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 SOD1 G93A mouse, a model of ALS, leads to dra-matic accumulation of ubiquitinated SOD1 G93A 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.

Original languageEnglish (US)
Pages (from-to)339-349
Number of pages11
JournalNeurodegenerative Diseases
Volume15
Issue number6
DOIs
StatePublished - Nov 24 2015
Externally publishedYes

Keywords

  • Aggregates
  • Aggresome
  • Amyotrophic lateral sclerosis
  • Autophagy
  • HDAC6
  • Lysosome
  • SOD1 mutant

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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