, 2004 and Vogiatzi et al., 2008). Interestingly, ubiquitination by the ligase Nedd4 has also been shown to target synuclein for degradation in the lysosome, rather than by the proteasome (Tofaris et al., 2011). Although we do not know how changes in the expression of synuclein may actually influence the development of human PD, recent work has suggested that changes in clearance may promote degeneration. In particular, idiopathic PD has been found to associate

with mutations in the glucocerebrosidase (GBA1) gene. Mutations in GBA1 are responsible for Gaucher’s find more disease, a recessive lysosomal storage disorder. However, the spectrum of phenotypes in Gaucher’s disease is very broad, with type 2 dying within the first 2 years of life and

type 1 surviving longer. Indeed, some of the so-called nonneuropathic type 1 patients eventually develop parkinsonism among other neurological Pexidartinib problems ( Alonso-Canovas et al., 2010 and Neudorfer et al., 1996). In addition, it has now become clear that heterozygotes with no overt symptoms of Gaucher’s disease develop PD at higher rates than controls. GBA1 mutations have been found in ∼7% patients with idiopathic PD, and up to ∼30% of Ashkenazi Jewish patients, with only 1.3% in the general population ( Sidransky and Lopez, 2012 and Sidransky et al., 2009). Mutations in GBA1 have also been reported in DLB but not MSA ( Farrer et al., 2009 and Segarane et al., 2009), supporting the difference in mechanism between MSA and Lewy related pathology. GBA1 mutations presumably increase susceptibility to PD by blocking the lysosomal degradation of α-synuclein ( Manning-Boğ et al., 2009), but it has been difficult to understand how a modest reduction in enzyme activity could impair lysosomal function enough to produce a degenerative disorder. Recent work has indeed suggested that α-synuclein accumulates

Digestive enzyme in both a mouse model of Gaucher’s disease and induced pluripotent (iPS) cells from patients with Gaucher’s disease but attributed the increase to aggregation in the presence of increased membrane glucocerebroside ( Mazzulli et al., 2011). Consistent with the localization of synuclein to lipid rafts (which are enriched in sphingolipids such as glucocerebroside) ( Fortin et al., 2004), and its preference for particular lipid acyl chains as well as head groups ( Davidson et al., 1998 and Kubo et al., 2005), the mechanism by which GBA1 mutations confer susceptibility to PD may involve specific effects on cell membranes rather than a more general disturbance in lysosomal function that simply upregulates the normal protein. Indeed, much of the work on synuclein has focused on its misfolding and aggregation. Since many publications have addressed the pathways to misfolding of α-synuclein, including several recent reviews ( Breydo et al., 2012, Goedert et al., 2013 and Lashuel et al.