238 dementia (FTD), and prion disease and are characterized by protein aggregation, inclusion body formation, and eventual significant neuronal loss. Our understanding of neurodegener- ative disease pathogenesis has been spurred by the conver- gence of two disciplines: the molecular characterization of aggregating proteins in the diseased brain, and the identifica- tion of familial forms of AD, PD, and FTD. PD is a debilitating neurodegenerative disorder charac- terized by a loss of neurons in the central nervous system (CNS), particularly the dopaminergic neurons of the substantia nigra pars compacta [1–6], but also in the locus coeruleus, nucleus basalis of Meynert, and the dorsal nucleus of the vagus nerve [7]. The majority of PD cases result from unknown etiology, with the loss of dopaminergic neurons of the substantia nigra pars compacta disrupting the basal ganglia network of the midbrain, striatum, and cortex. The disruption of the basal ganglia pathway leads to reduced thalamus activity, which in turn fails to adequately control cortical function through glutamatergic activation. The most noticeable and severe consequence of this signal disruption is a gradual decrease of motor cortex activity, especially in the primary motor cortex and the supplementary motor area. This gives rise to the cardinal PD clinical features of brady- kinesia, rigidity, and tremor, while loss of dopaminergic neurons in the olfactory bulb can lead to impairment of the sense of smell [1–6, 8–11]. In PD, protein aggregates known as Lewy bodies and Lewy neurites form in the neuronal soma and neuritic pro- jections, respectively. Since the identification of these lesions in the early 1920s and their subsequent characteriza- tion by electron microscopy as structures comprised of abnormal filaments in the 1960s, the presence of these protein aggregates was considered integral to the observed progressive CNS degeneration. However, the molecular mechanisms underlying the initiation and progression of PD remain largely elusive. Instrumental in our disease model conception has been the identification of patients with genetic variants that lead to autosomal-recessive or -dominant forms of the disease. Mutations in GBA, LRRK2, PARK2, PARK7 (DJ-1), PINK1, SNCA, or UCHL1 can lead to monogenic forms of PD or increased PD susceptibility, suggesting important roles for these proteins in the pathogenesis of the disease [12–17]. Of the distinct PD-related genetic alterations discovered, 500 relate to the five most prominently represented genes: SNCA, LRRK2, PARK2, PINK1, and PARK7, with genetic alterations in SNCA and LRRK2 leading to autosomal-dominant forms of the disease [12]. Notably, the genes identified in familial forms of PD, FTD, and AD are linked to the proteins that aggregate in both inherited and sporadic forms of those diseases. The first such mutation identified was a p.Ala53Thr mutation in the SNCA gene, which encodes α-synuclein, while subsequent studies have found that other SNCA Curr Neurol Neurosci Rep (2012) 12:237–242 mutants cause other inherited forms of PD. Intriguingly, Lewy bodies were independently found to be principally composed of the α-synuclein protein [18]. The existence of autosomal-dominant SNCA mutations in combination with the aggregation of the α-synuclein protein in the diseased brain, suggests a key and perhaps causal role for this protein—a conclusion that may extend to sporadic forms of PD. The remaining products of PD-related genes do not na- tively aggregate, but they can be linked in direct and indirect ways to protein degradation pathways: GBA encodes the key lysosomal protein β-glucocerebrosidase; LRRK2 encodes an enzyme called leucine-rich repeat kinase 2 that has a pre- dicted kinase activity, but is associated with the organization of lysosomes, endosomes, and other membranous organ- elles; PARK2 is part of the E3 ubiquitin-ligase complex; PARK7 protects cells against oxidative stress; PINK1 is hypothesized to be protective against cell stress by phos- phorylating mitochondrial proteins; UCHL1 is a neural- specific ubiquitin-protein hydrolase. Taken together, the genes affected by familial PD mutations yield an important foundation on which to build our understanding of this neurodegenerative disease. α-Synuclein and LRRK2 α-Synuclein is a 17-kD protein with two human homologs, β-synuclein and γ-synuclein. Robustly expressed through- out the CNS and peripheral nervous system (PNS), α- synuclein has long been considered to be a natively unstruc- tured protein that is capable of taking on partially folded amyloidogenic α-helical or β-sheet conformations [19]. However, more recent studies challenge this prevailing par- adigm, by suggesting that endogenous α-synuclein in non- denaturing conditions may form helically folded soluble tetramers that resist aggregation [20 ]. Although the exact function of α-synuclein remains un- known, the protein has been found in presynaptic vesicles, thus leading to its original nomenclature from the Torpedo ray. Further, α-synuclein has been shown to bind to lipids, potentially via its imperfect 11 amino-acid repeats, and associate with phospholipase D2 [21–23]. Taken together, these results implicate α-synuclein in neurotransmitter release, vesicle turnover, channel localization, and dose-dependent dynamic dopamine release [24]. Recently, Chandra et al. [25] and Burré et al. [26] demonstrated that α-synuclein is required for presynaptic vesicle chaperoning through SNARE-complex assembly by directly binding to VAMP2. These findings further support a neural-specific role for α-synuclein at the level of presynaptic vesicles. α-Synuclein knockout animals appear to be relatively unaffected—with conflicting literature reports suggesting