Tubulin appears to interact with a multimeric form of synuclein, and synuclein can influence the microtubule cytoskeleton (Lee et al., 2006). However, the functional ramifications of this interaction seem more relevant for the toxicity associated with synuclein

than for its normal function (Alim et al., 2002, Chen et al., 2007, Kim et al., 2008 and Lee et al., 2006). Since synuclein binds to membranes in an α-helical conformation, one interesting approach has been to use membrane-bound synuclein as a probe for conformation-specific Lumacaftor in vitro interacting proteins (Woods et al., 2007). This again resulted in the isolation of tubulin but also other proteins associated with the cytoskeleton. In addition, this approach identified one novel protein that is natively unfolded until membrane bound (Boettcher et al., 2008). More recently, the small GTPase rab3a has been proposed to regulate the membrane association of α-synuclein in a GTP-dependent manner (Chen et al., 2013), suggesting functional integration of synuclein into the cycling of this synaptic vesicle rab and hence into the synaptic Ku0059436 vesicle cycle. However,

the role of these potential regulatory mechanisms remains unclear, largely because we do not understand the normal function of synuclein. Although the normal function of synuclein remains elusive, the protein has a central role in multiple neurodegenerative processes. Indeed, the identification of mutations in α-synuclein has shifted the focus of work on the pathogenesis of PD from a specific defect in dopamine neurons to of a more widespread disturbance in the behavior of this protein. Previously, Lewy bodies had been detected by staining with hematoxylin

and eosin and with somewhat more sensitivity by immunostaining for ubiquitin. However, immunostaining for α-synuclein revealed much more widespread deposits in dystrophic neurites as well as Lewy bodies of cell populations not previously known to be affected (Galvin et al., 1999, Spillantini et al., 1997 and Spillantini et al., 1998b). In addition to demonstrating the relevance of synuclein for the idiopathic disorder, these observations have suggested a basis for the nonmotor manifestations of PD (Ahlskog, 2007, Dickson et al., 2009 and Jellinger, 2011). Constipation, hyposmia, depression, and rapid eye movement (REM) behavior disorder, which involves the loss of muscle atonia during REM sleep and hence unsuppressed motor activity while dreaming, can precede the onset of characteristic parkinsonian motor symptoms by up to two decades, consistent with the deposition of α-synuclein in the enteric nervous system, olfactory bulb, dorsal motor nucleus of the vagus, and glossopharyngeal nerves, as well as other brainstem nuclei (Postuma et al., 2012). Additional autonomic problems (e.g.