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.