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

Abstract

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 α-synuclein (α-Syn) in the pathogenesis of PD, and as such, there is intense interest in targeting α-Syn for potential disease modification. α-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 α-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 α-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 α-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.

Fig. 1

The structure of α-Syn. α-Syn is a 140-amino-acid (aa) protein composed of three domains: an N-terminal domain (aa 1–60), the NAC domain (aa 61–95), and a C-terminal domain (aa 96–140). There is a sequence of 11 residues that are repeated seven times found within the NAC and N-terminal domains. These repeats take on an amphipathic α helix secondary structure upon binding to lipids, which mediates the interaction of α-Syn with lipid membranes. All known disease-associated mutations are found in the N-terminal domain. There is also a confluence of glutamate residues and residues that are targets for phosphorylation in the C-terminal domain, which gives this domain a negative charge and may affect the propensity of α-Syn to misfold. Disease-associated mutations are marked in purple, and phosphorylation sites are marked in red.

Fig. 2

Approaches to reducing α-Syn toxicity. There are multiple points along the life cycle of α-Syn at which therapeutics may be used to intervene with its toxicity. These include reducing α-Syn transcription or translation, inhibiting α-Syn aggregation through the use of disaggregators, or interfering with proaggregation factors, enhancing α-Syn clearance and degradation through autophagy or the ubiquitin-proteasome system, decreasing release of α-Syn into the extracellular space, and targeting pathologic α-Syn through immunization. Another approach is to target other genes/proteins that influence α-Syn aggregation or processing, such as GBA, LRRK2, and PARP-1 (not pictured).