Loss-of-function, gain-of-function or a bit of both?
Loss-of-function and gain-of-function hypotheses are not irreconcilable. The absence of an overt parkinsonian phenotype and DA neuron degeneration in germline α-syn knockout mice does not directly address the loss-of-function hypothesis. Whole genome expression analysis of SNCA(−/−) mice identified differential expression of 369 transcripts as compared to wild-type animals (Kuhn et al., 2007). This includes increased expression of transcripts of other synuclein family members, 14-3-3 proteins, TH and neurotrophic factors, decreased expression of pro-apoptotic transcripts, and changes in genes directly involved in vesicle function and neurotransmission. Thus, the lack of a severe phenotype in these animals is likely the result of complex germline compensation for α-syn function. While heritable forms of PD associated with duplication and triplication of the SNCA gene arguably support the toxic gain-of-function hypothesis, germline α-syn overexpression mice do not directly support this contention. The available mouse models exhibit little or no degeneration of SN DA neurons, although similar to α-syn knockout mice, show prominent changes in striatal DA neurotransmission (e.g., Chesselet and Richter, 2011; Crabtree and Zhang, 2012 for reviews). Nevertheless, if the α-syn transgene is induced in the mature animal, nigral degeneration does occur (Lin et al., 2012). Thus, it is plausible that germline compensation, similar to that seen in the knockout, occurs in overexpression transgenic models as well.
While germline transgenic models do little to inform the toxic gain-of-function/loss-of-function debate it is inarguable that too much α-syn and mutant α-syn can produce direct neurotoxicity. In vitro studies demonstrate that specific conformations of α-syn exert cytotoxic effects by permeabilizing vesicles, altering calcium flux, impairing mitochondrial function, and inducing apoptosis (Volles et al., 2001; Pieri et al., 2012; Luth et al., 2014; Pacheco et al., 2015). In addition, viral vector-mediated overexpression of α-syn in DA neurons uniformly produces significant, albeit variable in magnitude, neurodegeneration (e.g., Van der Perren et al., 2014 for review). However, in this case it is unclear what precipitates neurodegeneration. Nonetheless, in line with our hypothesis, and with data gained from the PFF model (i.e., Osterberg et al., 2015) it is plausible that loss of soluble endogenous α-syn to aggregation is one contributor to neurotoxicity. Thus, experimental support for both viewpoints suggests a “Goldilocks” biology commonly exhibited by many molecules: too much is bad, too little is bad, enough is just right (Kanaan and Manfredsson, 2012).