Immunotherapy for synuclein in Parkinson's disease

抄録

Progressive accumulation of α-synuclein (α-syn) has been associated with Parkinson's Disease (PD) and Dementia with Lewy Body (DLB). The mechanisms through which α-syn leads to neurodegeneration are not completely clear; however, formation of various oligomeric species have been proposed to play a role. Antibody therapy has shown effectiveness at reducing α-syn accumulation in the CNS. Both active and passive immunization strategies have been utilized in animal models and human patients to alleviate the effects of toxic protein aggregation associated with various neurodegenerative diseases. Initial immunotherapeutic studies showed that vaccination with full-length human α-syn protein in α-syn tg mouse models of DLB decreased accumulation of aggregated α-syn and reduced neurodegeneration. Likewise, passive immunization with antibodies against α-syn reduced memory and neurodegenerative deficits by promoting clearance of α-syn via autophagy or microglia-dependent degradation. Furthermore, immunization to certain epitopes of α-syn also reduce α-syn propagation to glial and neuronal cells. We and others have also investigated the use of conformation specific antibodies that recognize only oligomeric versus monomeric or fibrilar α-syn. To date, immunotherapeutic approaches suggest a viable therapeutic approach for the treatment of neurodegenerative diseases that progress with the accumulation and prion-like propagation of toxic protein aggregates.