Molecular chaperones and degradation systems allow cells to cope with misfolded and genetically mutated proteins. The Hsp70/Hsp40 families and the members of the HspB family (HspB1-HspB10) recognize and bind misfolded proteins, prevent their aggregation and facilitate their degradation. Mutations in genes encoding several HspB proteins have been associated with neurological and muscular disorders, strongly supporting a critical role for these proteins in neuronal and muscular cell viability. For this project, we focus on HspB8, which is mutated in peripheral neuropathies. However the precise mechanisms leading to disease progression are largely unknown. Inversely, I found that upregulation of HspB8 in cell systems can ameliorate toxic aggregation of proteins related to polyglutamine diseases, like Huntington disease (HD) or Spinocerebellar ataxias (SCAs). Our data suggest that HspB8 plays a role in autophagy, which deregulation may contribute to neurodegeneration and which upregulation may explain its effects on HD and SCA. In these actions, I found that HspB8 cooperates in a non-canonical manner with Bag3, independent of its classical interaction partners Hsp70 and Bcl-2. I will further analyse connections of HspB8/Bag3 with other HspB members and how they influence autophagy using different in vitro approaches. Recently, we also identified the Drosophila HspB8 orthologue and show that it interacts with Starvin, the Drosophila Bag3 orthologue. This will allow us to evaluate the effects of the complex in vivo and to establish whether the progression of peripheral neuropathies is due to a toxic gain of function (overexpression of mutated HspB8) or to a loss of the HspB8 chaperone activity (knock-out of HspB8) and whether deregulated autophagy is involved in the development of the disease. Finally, crossing our strains with Drosophila models of HD and SCA will allow us establishing whether overexpression of the complex can also inhibit HD or SCA progression.
Field of science
- /natural sciences/biological sciences/genetics and heredity/mutation
- /natural sciences/biological sciences/biochemistry/biomolecules/proteins
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