Even proteins need chaperones The bundling of misfolded proteins is a major characteristic of many degenerative diseases. Autophagy can help offset this aggregation of mutated proteins. Health © Shutterstock Molecular chaperones can be employed to identify and attach to misfolded proteins so as to prevent their accumulation. A degradation mechanism can be set in motion by stimulating autophagy. This helps cells cope with misfolded proteins and ensure neuronal survival. HspB is one such family of molecular chaperones. HspB1-HspB10 members are known to facilitate the degradation of misfolded proteins. Genetic mutations in genes encoding some of these are linked to neuropathies and myopathies. This suggests that they play a major role in the life cycle of neuronal and muscular cells. The 'Role of the HspB8/Bag3 chaperone complex in neurodegenerative disorders' (HspB8 and neuropathy) project is studying HspB8. Although it is known to be mutated in peripheral neuropathies, the exact processes that lead to development of disease are still unclear. Prior research has shown that upregulation of HspB8 in cell systems can ease toxic protein aggregation, which is related to diseases such as Huntington's (HD) or spinocerebellar ataxias (SCAs). The main aim of this project is to discover whether alterations brought about in the functioning of the HSPB8-BAG3 chaperone complex can serve to protect against these kinds of disorders. Data suggest that overexpressing HSPB8-BAG3 can prevent aggregation and facilitate degradation by stimulating autophagy. In these actions, HspB8 forms a stable complex with the co-chaperone BAG3. In other studies done so far, the team has successfully identified the dynamics of HSPB8-BAG3, autophagy and the eIF2 alpha pathway. Results showed that inhibition of the regulation of protein function at the eIF2alpha level can fully annul the effects of HSPB8-BAG3 on autophagy. Other in vivo studies using a cell model of different mutants revealed that overexpression of human HSPB8 weakens aggregation activity and can protect against degeneration. HspB8 and neuropathy partners continue to work towards a comprehensive description of how the HSPB8-BAG3 complex can be used to influence the control of protein quality and autophagy. Successes in this area promise to enhance understanding of how HSPB8 mutations lead to peripheral neuropathies.
