Abstract
The cellular protein quality control system in association with aggresome formation contributes to protecting cells against aggregation-prone protein-induced toxicity. p62/Sequestosome 1 (p62) is a multifunctional protein which plays an important role in protein degradation and aggregation. Although poly-ubiquitination is usually required for p62-mediated protein degradation and aggresome formation, several p62 substrates are processed to form aggregate in an ubiquitination-independent manner. In this study we demonstrate that p62 directly interacts with pathogenic Machado Joseph Disease (MJD)-associated protein ataxin-3 with polyglutamine (polyQ) expansion. Moreover, p62 could regulate the aggresome formation of pathogenic ataxin-3 and protect cells against pathogenic ataxin-3-induced cell death.
Highlights
Machado Joseph Disease (MJD)/Spinocerebellar ataxia type 3 (SCA3), the most common SCA subtype, is a polyglutamine disease caused by the expansion of a CAG stretch in MJD1 gene [1,2]
We found that p62 can regulate aggresome formation of pathogenic ataxin-3, and p62 physically interacts with pathogenic ataxin-3, but not normal ataxin-3
The aggregation of polyQ expanded ataxin-3 is a neuropathological hallmark of MJD [11,12], and p62 is known to be recruited to those ataxin-3 inclusions in MJD patient brains [10]
Summary
Machado Joseph Disease (MJD)/Spinocerebellar ataxia type 3 (SCA3), the most common SCA subtype, is a polyglutamine disease caused by the expansion of a CAG stretch in MJD1 gene [1,2]. It has been reported that the aggregates can be transported along microtubule towards microtubule organizing center (MTOC) to generate a large inclusion structure named aggresome. This process is usually thought to protect cells against the aggregated protein-induced cell death [13,14,15], and aggresomes formed by pathological proteins have been broadly discovered in neurodegenerative diseases, such as synphilin-1 and DJ-1 aggresomes in Parkinson’s disease, huntingtin aggresomes in Huntington’s disease and copper-zinc superoxide dismutase (SOD1) aggresomes in amyotrophic lateral sclerosis (ALS), respectively [15,16,17,18,19,20,21]. Up to date, it is still unknown whether pathogenic ataxin-3 could form aggresomes
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