Alpha-synuclein in Parkinson's disease
The best-validated participant in the molecular pathology of Parkinson's disease (PD) is alpha-synuclein (α-syn). Mutations and multiplications of the α-syn SNCA gene locus both produce inherited forms of PD (Polymeropoulos et al., 1997; Singleton et al., 2003; Ibanez et al., 2004). In addition, the presence of α-syn in Lewy bodies and neurites of midbrain dopamine (DA) neurons, the histological hallmark of PD, provides evidence for its association with idiopathic PD (Spillantini et al., 1997). While a pervasive viewpoint postulates that excess α-syn and consequent aggregation directly fuels neurotoxicity in a toxic gain-of-function event, it also is acknowledged that α-syn aggregation may endanger neurons by removing the protein from its normal cellular location and diminishing its function in a toxic loss-of-function event (Perez and Hastings, 2004; Cookson, 2006; Kanaan and Manfredsson, 2012). This issue remains a topic of debate.
Despite this ambiguity, approaches that may indiscriminately reduce α-syn in the central nervous system represent an active area of research as an approach for treating PD (e.g., AFFiRiS PD01, Prothena/Roche PRX002). In this Hypothesis and Theory article, we discuss evidence from rodent and non-human primate experiments suggesting that Parkinson's-like degeneration of the nigrostriatal DA system can be reproduced by eliminating endogenous α-syn from DA neurons vulnerable to degeneration in PD. These studies support the tentative conclusion that α-syn elimination therapies that do not distinguish between native and abnormal forms may compromise the viability of DA neurons and should proceed with caution.