Abstract
The role of protein aggregates, such as Lewy body inclusions, in the molecular pathogenesis of Parkinson’s disease has remained controversial and elusive. The protein α-synuclein is a major component of these inclusions but it can exist in many alternate conformations. Here we review advances in our understanding of the roles of Lewy pathology and α-synuclein in Parkinson’s disease. Recent work has demonstrated that certain α-synuclein conformations are directly toxic to neurons and may also propagate Lewy pathology within the nervous system. Investigation into clinicopathological correlates in rare genetic forms of Parkinson’s disease has revealed that Lewy pathology is associated with nonmotor features but may not contribute to motor symptoms in Parkinson’s disease. These recent findings open up new avenues of investigation into the molecular pathogenesis of Parkinson’s disease. Future work will need to identify the most toxic conformations of α-synuclein and define their relationship to Lewy pathology. This work will be necessary to be able to develop novel therapeutic strategies that target specific pathogenic forms of α-synuclein for disease modification in Parkinson’s disease.