Therapeutics in the Pipeline Targeting α-Synuclein for Parkinson's Disease

Parkinson's disease (PD) is the second most common neurodegenerative disorder and the fastest growing neurologic disease in the world, yet no disease-modifying therapy is available for this disabling condition. Multiple lines of evidence implicate the protein alpha-synuclein (alpha-Syn) in the pathogenesis of PD, and as such, there is intense interest in targeting alpha-Syn for potential disease modification. alpha-Syn is also a key pathogenic protein in other synucleionpathies, most commonly dementia with Lewy bodies. Thus, therapeutics targeting this protein will have utility in these disorders as well. Here we discuss the various approaches that are being investigated to prevent and mitigate alpha-Syn toxicity in PD, including clearing its pathologic aggregates from the brain using immunization strategies, inhibiting its misfolding and aggregation, reducing its expression level, enhancing cellular clearance mechanisms, preventing its cell-to-cell transmission within the brain and perhaps from the periphery, and targeting other proteins associated with or implicated in PD that contribute to alpha-Syn toxicity. We also discuss the therapeutics in the pipeline that harness these strategies. Finally, we discuss the challenges and opportunities for the field in the discovery and development of therapeutics for disease modification in PD. Significance Statement-PD is the second most common neurodegenerative disorder, for which disease-modifying therapies remain a major unmet need. A large body of evidence points to alpha-synuclein as a key pathogenic protein in this disease as well as in dementia with Lewy bodies, making it of leading therapeutic interest. This review discusses the various approaches being investigated and progress made to date toward discovering and developing therapeutics that would slow and stop progression of these disabling diseases.