Dra. Catalina Requejo | Department of Neurology, The Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York.
Parkinson's disease (PD) is characterized by the accumulation of intraneuronal Lewy bodies (LB) that contain insoluble fibrillar aggregates of ?-synuclein, and the selective degeneration of the midbrain dopaminergic neurons. In fact, striatal ?-synuclein preformed fibrils (PFF) injection in non-transgenic mice leads to alpha-synuclein pathology. Despite the mechanisms involved in alpha-synuclein transmission remain unclear; aberrant autophagy is emerging as a causative factor of the dissemination of synucleinopathies. Therefore, the use of genetic models of PD in which autophagy is disrupted, could provide better understanding of the pathogenic mechanisms underlying the progression of ?-synuclein pathology. Here we are thus focusing on determining which mechanisms are activated in the clearance of alpha-synuclein either using genetic related PD models or autophagy-deficient mouse models receiving alpha-syn PFF.
To achieve these aims we use a PLA2G6 deficient mouse model to assess the role of inflammatory response in alpha-syn accumulation, and due to p62 is an autophagy receptor present in LB, we also used p62 KO mice intrastriatally administered with ?- syn PFF to elucidate how the p62 ablation may affect in alpha-syn pathology. Our findings indicated that not only p62 ablation reduced the alpha-syn spreading throughout the brain, but also uptake of PFF by neurons is significantly reduced in the absence of p62 and seeding the endogenous a-syn is thus reduced. On the other hand, the absence of PLA2G6 caused widespread reactive gliosis, higher cytokine mRNA expression in PLA2G6 KO microglia as well as an incipient microgliosis and accumulation of p62 and alpha-syn in clustered microglia.
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