Function and Pathogenic Mechanism of alpha-synuclein in Parkinson's Disease

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Parkinsons disease (PD) is pathologically characterized by a preferential loss of midbrain dopaminergic (mDA) neurons and the presence of alpha-synuclein (alpha-syn)-positive intracytoplasmic inclusions named Lewy bodies (LBs) and Lewy neurites (LNs) (Schapira, 1997;Spillantini et al., 1997). While both missense and multiplication mutations of alpha-syn cause early-onset autosomal dominant familial form of PD, the alpha-syn gene locus also associates with the more common sporadic PD (Polymeropoulos et al., 1997;Singleton et al., 2003;Simon-Sanchez et al., 2009;Satake et al., 2009). Together, these genetic and pathological studies clearly point out an important role of alpha-syn in the pathogenesis of PD. Extensive studies have been performed to understand the underlying pathogenic mechanisms of alpha-syn-induced cell loss. It has been shown that over-expression of both wild-type and PD-related mutant alpha-syn leads to a variety of cytotoxicity, including the impairment of proteasome and lysosome activities (Cuervo et al., 2004;Stefanis et al., 2001;Tanaka et al., 2001;Chen et al., 2006), the disruption of ER-Golgi transport (Cooper et al., 2006;Gosavi et al., 2002;Lin et al., 2009), the perturbation of the mitochondrial function (Hsu et al., 2000;Martin et al., 2006;Song et al., 2004;Nakamura et al., 2011), and the inhibition of synaptic transmission (Nemani et al., 2010). However, most of these results were obtained from cell lines and non-mDA neurons. It remains to determine whether these pathogenic pathways are pathophysiologically relevant to the degeneration of mDA neurons. While the loss of nigral DA neurons underlie the main motor syndrome of PD, the progress of PD research has been especially hindered by a lack of effective mouse genetic model that carries PD-related genetic mutations and develops progressive degeneration of mDA neurons (Hisahara and Shimohama, 2010). Many lines of PD-related mutant alpha-syn transgenic mice have been generated previously; however, few of them exhibited robust and progressive degeneration of mDA neurons (Kahle et al., 2001;van der et al., 2000;Matsuoka et al., 2001;Lee et al., 2002;Lin et al., 2009;Chesselet, 2008;Harvey et al., 2008;Richfield et al., 2002;Gispert et al., 2003;Wakamatsu et al., 2008;Thiruchelvam et al., 2004). Noticeably, only a scarce or low levels of transgenic alpha-syn expression were observed in the mDA neurons of these mutant mice, in which the transgenic alpha-syn is often under the transcriptional control of pan neuronal promoters or a rat tyrosine hydroxylase (TH) promoter. To investigate the pathogenic mechanism of alpha-syn-dependent dopaminergic dysfunction in vivo, we generated a new line of alpha-syn transgenic mice by driving the expression of PD-related A53T alpha-syn in the mDA neurons using a binary tetracycline-dependent inducible gene expression system. The mutant mice developed profound movement disorders as well as robust and progressive mDA neurodegeneration, which thereby may provide a valuable mouse genetic model to investigate how alpha-syn induces the degeneration of mDA neurons. Towards to this direction, we systematically examined the alpha-syn-mediated subcellular abnormalities in the mDA neurons of mutant mice. Moreover, we identified nuclear receptor related 1 protein (Nurr1), a master transcription factor for the development and maintenance of mDA neurons, as a key downstream molecular target for the alpha-syn-induced preferential degeneration of mDA neurons. A contribution of Nurr1 dysfunction in PD has been proposed previously (Le et al., 2003;Chu et al., 2002;Baptista et al., 2003). We extended these early studies and demonstrated that over-expression of both wild-type and A53T alpha-syn promoted a proteasome-dependent degradation of Nurr1. We further demonstrated that inhibition of proteasome-mediated degradation of Nurr1 ameliorated alpha-syn-induced loss of mDA neurons. These data suggest that the suppression of Nurr1 protein expression by alpha-syn is a key molecular determinant for the preferential dysfunction and loss of mDA neurons in PD. In line with this notion, a conditional deletion of Nurr1 in the mDA neurons results in a very similar rearing impairments and mDA neurodegeneration compared to the A53T conditional transgenic mice (Kadkhodaei et al., 2009). Multiple post-translational modifications have been found to modulate the stability and function of Nurr1 protein, including phosphorylation, ubiquitination (Jo et al., 2009), sumoylation (Galleguillos et al., 2004), and acetylation (Kang et al., 2010). alpha-syn may regulate the degradation of Nurr1 protein through various molecular cascades. In addition, it remains to determine whether other PD-related genes also affect the expression and stability of Nurr1 protein in PD. In summary, this study describes a new line of alpha-syn A53T transgenic mice that display robust and progressive degeneration of mDA neurons. The dynamic regulation of Nurr1 protein stability by alpha-syn in the mDA neurons may not only help to address the molecular mechanism of the preferential susceptibility of mDA neurons in PD, but may also provide new therapeutic targets for the treatment of the disease.