Three different point mutations in α-synuclein, A.53T, A30P, and E46K, have been associated with PD in separate families with dominantly transmitted PD.5,10,11 These are gain-of-function mutations. There is also evidence that oc-synuclcin promoter variants contribute to the lifetime risk of sporadic PD.12-14 In general, alleles that increase α-synuclein expression are associated with an increased risk for PD. Recent work has shown that, triplication of the α-synuclcin gene is sufficient to cause PD and, in human postmortem

brain, is accompanied by doubling of α-synuclein protein expression.15,16 Similarly, postmortem studies in sporadic PD show that Inhibitors,research,lifescience,medical α-synuclein mRNA is upregulatcd in the SNpc of affected individuals.17 The link between α-synuclein and sporadic PD is found in Lewy bodies (LBs), the pathological hallmark of PD, since α-synuclein has been shown to be the primary constituent of LBs.18-22 LBs are eosinophilic fibrillar cytoplasmic inclusions in DA neurons that can be detected in both the SNpc and the cortex of PD patients (Figure Inhibitors,research,lifescience,medical 2). LBs are located in the cell body, axons, and dendrites of Inhibitors,research,lifescience,medical neurons, and are composed of neurofilaments 7 to 25 nm in diameter; these neurofilaments

are believed to be inappropriately phosphorylated, proteolytically truncated, and ubiquitinatcd.23 LBs have been meantime reported to include a wide range of proteins (including ubiquitin, parkin, and tau), heat, shock proteins (HSPs), torsin A, neurofilaments, oxidized/nitrated proteins, proteasomal elements, and others.22,24-31 Interestingly, many proteins that interact with α-synuclein and parkin have also been identified as components of LBs, for instance, parkinassociated endothelin-like Inhibitors,research,lifescience,medical receptor (Pael-R; a transmembrane polypeptide),32 synphilin-1,33 and p38 (a structural component of the mammalian am.inoacyl-t.RNA synthetase complex).34 LBs ectopically express the cell cycle protein cyclin B; this may be related to cyclin B’s interaction with oc-synuclcin, which predisposes nigral LB-bearing

Inhibitors,research,lifescience,medical DA neurons to undergo apoptosis.35 Another protein colocalized with α-synuclein in LBs is inhibitor Seliciclib tissue transglutaminase (tTGase), which induces cross-linking of oc-synuclcin in vitro.36 tTGase inhibition could therefore be a novel therapeutic target in PD, provided that. LB formation is indeed a cytotoxic event. Figure 2. A Lewy body (LB). The LB is shown as a dense eosinophilic Cilengitide inclusion bordered by neuromelanin, the auto-oxidation product of dopamine (DA), which allows identification of DA neurons in the human substantia nigra pars compacta (SNpc). Parkin is widely distributed protein in DA and non-DA neurons in normal human brain and in sporadic PD. It is mostly located in large cytoplasmic vesicles and in the endoplasmic reticulum (RR).37 The initial postmortem studies from five parkin-positive cases initially failed to find LBs – an observation used to argue that parkin is required for LB formation.