Modulation of α-synuclein aggregation and toxicity

Dissertação para obtenção do Grau de Mestre em Genética Molecular e Biomedicina

It is widely known that α-synuclein (aSyn) is an amyloidogenic protein prone to aggregation. This protein is found in specific inclusions named Lewy bodies in the surviving neurons of Parkinsons’s disease patients and other synucleinopathy brains. This aggregation process is greatly affected by different post-translational modifications, such as phosphorylation, acetylation, and glycation. Lately it was shown that aSyn oligomeric species are more toxic than the inclusion bodies. Heat shock proteins (HSPs) are molecular chaperones able to modulate the folding and refolding of proteins. Its overexpression in Parkinson’s disease models reduces and prevents aSyn aggregation. As the reduction of aSyn aggregation can lead to an eventual accumulation of oligomeric species which may cause cell damage, the main goal of this work is to better understand the role of HSPs in aSyn oligomer formation, clarifying which are the aSyn resulting species formed in the presence of HSPs. Moreover, as glycation is suggested to accelerate abnormal protein deposition, we aimed to investigate how HSPs interfere with the oligomerization process of glycated aSyn. In this study Hsp70 seemed to induce recombinant aSyn oligomerization, generating higher molecular weight species with no associated toxicity. On the other hand, Hsp27 reduced aSyn oligomerization in vitro possibly by inducing the formation of non-reactive small oligomers. MGO glycation increased protein aggregation and cell death. Interestingly, Hsp27 overexpression reversed glycated aSyn aggregation and its associated toxicity. These results demonstrate the importance of HSPs modulation as a possible target of Parkinson’s disease therapeutics.