YOUNG INVESTIGATOR Award

Carra Serena, PhD

University Medical Center Groningen, The Netherlands
Role of small heat shock proteins (HspB) in the prevention of mutant ataxin-3 aggregation and toxicity.

Many of the most common neurodegenerative disorders including polyglutamine diseases, such as SCA-3/Machado-Joseph disease are characterized by the aggregation and accumulation of misfolded proteins. By interacting with essential cellular components, mutated proteins can entrap these elements into aggregates, thus contributing to the cascade of neurotoxic events which finally leads to neuronal death. A protective role for molecular chaperones, including Hsps and HspB, against mutated protein toxicity has been extensively demonstrated. In the presence of mutated and instable proteins, which are more prone to aggregate, molecular chaperones avoid their accumulation and/or target them for degradation. Recently, a major role for the autophagy has been recently proposed in the degradation of mutated polyglutamine proteins,
including mutated ataxin-3, but little evidence exists demonstrating a role for molecular chaperones in modulating the autophagy-mediated degradation of misfolded proteins. We previously reported that HspB8, member of the HspB family (HspB1-HspB10), blocked mutated
polyglutamine proteins (huntingtin, androgen receptor and ataxin-3) aggregation. We recently found that HspB8 forms a stable complex with Bag3. Overexpression of the HspB8/Bag3 chaperone complex inhibited the aggregation of mutated huntingtin and, most importantly,
stimulated its degradation through the autophagy pathway. In parallel, we observed that Bag3 can function in the absence of HspB8, thus strongly suggesting that it may cooperate with other members of the HspB family. We will identify the chaperone complexes that facilitate the
autophagy-mediated clearance of mutated ataxin-3 and we will analyze their expression levels in tissues and cell cultures from patients affected by the Machado-Joseph disease. This will allow us to focus our future studies on the HspB proteins whose profile is altered in the disease. The selective upregulation of the HspB complexes able to facilitate mutated ataxin-3 degradation by autophagy may have relevant therapeutic implications. In fact, mutations in several HspB cause neurodegeneration, suggesting that they may have important neuroprotective functions. Moreover, accumulation of mutated ataxin-3 within the nucleus is required for the manifestation of the symptoms, supporting the hypothesis that facilitating its autophagy-mediated degradation may contribute to slow down the disease progression.