As anticipated from the structural studies, one report has shown that membrane association inhibits synuclein oligomerization (Zhu and Fink, 2003), but others have suggested that oligomerization occurs on membranes (Jo et al., 2000 and Lee et al., 2002a) and can be promoted by polyunsaturated fatty acids (Perrin et al., 2001). It is important to recognize that the oligomers formed on membranes may be helical, as suggested by the recent work using nanoparticles (Varkey

et al., 2013); however, recent NMR and EM have shown directly Thiazovivin mw that anionic phospholipid membranes can convert helical α-synuclein into fibrils (Comellas et al., 2012). It will now be important to determine how membranes influence the conformation and oligomerization of synuclein in cells. Careful neuropathologic examination of synuclein deposition in brains with Lewy pathology (from incidental

Lewy body disease to end-stage PD) has suggested that the degenerative process advances through the nervous system along specific anatomic pathways (Braak et al., 2003). The first synuclein deposits arise in either the dorsal motor nucleus of the glossopharyngeal and vagal nerves or the olfactory bulb (stage 1). In stage 2, the medulla and pontine tegmentum develop Lewy pathology and only in stage 3 does synuclein deposition occur in the midbrain as well as amygdala. At this point, the typical motor manifestations of PD generally appear. In stage 4, α-synuclein deposits in temporal cortex, and in stages 5 and Selleckchem Inhibitor Library 6 in neocortex, presumably contributing to the cognitive deficits observed in LBD and advanced PD. A minority of cases do not fit this pattern, and isolated

Lewy pathology can arise in the amygdala of patients with AD, but the progression otherwise appears quite Bay 11-7085 stereotyped (Dickson et al., 2010). The Braak staging of Lewy pathology presumably accounts for the development of symptoms such as hyposmia and REM behavior disorder up to decades before the onset of typical parkinsonism. It has also suggested a portal of entry for the disease in either the olfactory mucosa or the gastrointestinal tract. Indeed, the retrospective analysis of routine colon biopsies has recently shown synuclein deposits in the enteric nervous system years before the clinical onset of PD, suggesting a useful and accessible biomarker (Shannon et al., 2012). However, it remains unclear whether the process originates in the gut, spreading to the CNS through the vagal nerves rather than the spinal cord, or arises independently at multiple sites in sympathetic as well as parasympathetic nerves (Bloch et al., 2006, Iwanaga et al., 1999 and Orimo et al., 2008).