Alpha-synuclein and immune system crosstalk in parkinson's disease; therapeutic approaches of its modulation by molecular chaperones

Abstract

This Doctoral Thesis is focused on the interplay between the immune system and the Parkinson’s related protein alpha-Synuclein. The first part of this work was to study the impact of extracellular aSyn priming on the microglial innate immune response following TLR stimulation. As a result we found that extracellular non-aggregated alpha-synuclein could potentially act as a priming factor for microglia to produce exacerbated TLR7 and TLR1/2 responses upon further challenge as compared to the same challenge in the absence of such priming. The second part of my PhD study was centred in testing immunotherapeutic approaches for Parkinson’s Disease. During the last decade, it has become accepted that there is a link between alpha-synuclein and the sustained neuroinflammation and immune imbalance associated to Parkinson’s disease. As a result, different approximations have been tested to try to restore it. Molecular chaperones have a key role in preventing abnormal protein aggregation by interacting with misfolding proteins, including alpha-synuclein. On the other hand, several members of the chaperome network have shown immune modulatory capabilities and to be potentially useful for treating cancer and certain infections. In order to put in common these two features, which are particularly relevant for PD and other neurodegenerative misfolding diseases, I have characterized the peripheral immune response generated by immunization with the complex-forming Hsp70 and aSyn combination in the absence of added adjuvant. (A.Labrador-Garrido et al. IID 2014); performed a screen of a large set of chaperones on their immune-modulatory capabilities to find other promising candidates, as a result of the screen I have characterized the peripheral immune response elicited by immunization of healthy mice with Grp94 or FKBP4, two selected chaperone candidates (A.Labrador-Garrido et al. FASEBJ 2015). Finally we decided to investigate the peripheral immune response and the associated immunity at the CNS level, elicited in a PD mouse model by prophylactic immunization with Grp94 in combination with monomeric aSyn (A.Labrador-Garrido*, J.Villadiego*, el al. JNeurosci 2017 –in preparation-)