, 2005 and Yazawa et al., 2005). Remarkably, α-synuclein is not normally expressed by oligodendrocytes

(Miller et al., 2005), selleck screening library and a fundamental question remains about the origin of this protein: is it taken up from neurons, or does the pathological process activate expression by glia? In fact, the pathology shows relatively little deposition of synuclein in neurons, with only occasional nuclear and cytoplasmic inclusions (Farrer et al., 2004, Jellinger and Lantos, 2010 and Nishie et al., 2004b). At the same time, oligodendrocytes do not seem to upregulate expression of α-synuclein even in MSA (Miller et al., 2005). Regardless of its source, α-synuclein accumulates to particularly high levels in MSA, Regorafenib solubility dmso suggesting a process distinct from Lewy pathology. In addition, GCI lesions are widespread in MSA but generally correlate with neuron loss in the substantia nigra, pons, cerebellum, and intermediolateral cell columns of the spinal cord, suggesting that the glial process may be primary. MSA is rarely familial (Soma et al., 2006) and mutations in α-synuclein have not been observed (Ozawa et al., 2006). However, polymorphisms in the synuclein gene may influence susceptibility to MSA (Al-Chalabi

et al., 2009 and Scholz et al., 2009). In addition, the analysis of familial MSA has recently identified mutations in COQ2, a protein required for the synthesis of coenzyme Q10 (Multiple-System Atrophy Research Collaboration, 2013). The degenerative process in MSA may thus reflect a primary lesion in mitochondria. DLB more closely resembles idiopathic PD in terms of Lewy body

pathology. Although DLB appears to be a distinct syndrome, with early cognitive impairment, fluctuating alertness, and visual hallucinations in addition to progressive parkinsonism, the distribution of Lewy pathology appears remarkably similar to that observed in PD, with a brainstem-predominant form and others involving the cortex as well (McKeith et al., 2005). Like PD and MSA, DLB also involves primarily the deposition of α-synuclein. Lewy pathology was originally considered to involve only α-synuclein, but β- and γ- can deposit in both PD and DLB (Galvin et al., 1999). Similar to α-synuclein, β- accumulates presynaptically in PD, but γ- forms axonal spheroids. β-synuclein has been suggested to ameliorate GBA3 the toxicity of α-synuclein by reducing either its aggregation or its expression (Fan et al., 2006 and Hashimoto et al., 2001). However, polymorphisms in β-synuclein predispose to DLB (Ohtake et al., 2004), and transgenic mice overexpressing the variant develop degeneration and behavioral abnormalities (Fujita et al., 2010). These animals do not develop typical Lewy pathology, but they do accumulate both α- and β-synuclein in axonal spheroids (Fujita et al., 2010). Indeed, β-synuclein appears as toxic as α-synuclein to cultured neurons (Taschenberger et al., 2013).