a-Synuclein is expressed throughout the brain, with high levels in the olfactory bulb, cerebral cortex, striatum, hippocampus, and at lower levels in the thalamus (11). a-Synuclein is quite abundant in the brain, and has been estimated to be as much as 1% of total soluble brain protein (11). a-Synuclein is also expressed in other cell types, such as platelets (36) and neurons of the cardiac plexus (37). ß-Synuclein is expressed throughout the brain at high levels, and at low levels in the peripheral nervous system and skeletal muscle (10,38). /-Synuclein is also expressed at high levels in the brain, particularly the brainstem (39), at moderate levels in the heart and skeletal muscle, and at low levels in the peripheral nervous system, pancreas, kidneys, and lungs (38). /-Synuclein is also highly up regulated in advanced infiltrating breast cancer tissue, indicating that it may play a role in late-stage cancer progression (40).

a-Synuclein was originally characterized as both a nuclear and synaptic protein (16); subsequent studies with more specific antibodies revealed that both a- and ß-synuclein are primarily localized to synaptic terminals (10,11). a-Synuclein behaves similarly to a weak, vesicle-associated protein during biochemical fractionation experiments; however, a-synuclein is not present in purified synaptic vesicle preparations (17). Electron microscopy of rat brains, reveals that a-synuclein is associated with, or in close proximity to, synaptic vesicles. /-Synuclein, in contrast to a- and ß-synuclein, does not appear to be specifically localized to synaptic terminals. 7-Synuclein is cytosolic and present in cell bodies, processes, and growth cones of cultured dorsal root ganglia neurons, and is present in cell bodies and axons of sensory neurons (39).

Developmentally, a-synuclein is first expressed between 15 and 17 weeks gestational age, with initial localization to the cell body and processes, which shifts to an exclusively synaptic localization by week 18 of gestation (41). The absence of initial a-synuclein expression and the viability of a-synuclein knockout mice (42) indicate that a-synuclein is not essential for synaptic development or survival.

The normal function of a-synuclein is currently unknown. a-Synuclein knockout mice are healthy and fertile and have normal brain anatomy. However, these mice display an increased release of dopamine at nigro-striatal terminals in response to paired stimuli. These mice also display an attenuation of locomotor responses in response to amphetamine (42). These observations indicate that a-synuclein may be involved in regulation of dopamine neurotransmission. However, a- and ft-synuclein double knockout mice do not have any detectable phenotypes, and the effects on dopamine neurotransmission were not observed in these bigenic mice (43). Studies have shown that these knockout mice have a depleted, undocked vesicle pool in hippocampal synapses, indicating that a-synuclein may be involved in maintenance of the "reserve" presynaptic vesicle pool (44), as initially suggested in studies of cultured wild-type rodent hippocampal neurons (45). a-Synuclein can also regulate the amount of dopamine transporter (DAT) in the plasma membrane. Expression of a-synuclein has the ability to both increase (46) and decrease (47) trafficking of DAT to the plasma membrane. Direct binding of the NAC region of a-synuclein to the C-terminal region of DAT has been demonstrated through coimmunoprecipitation studies (48). The A30P mutation of a-synuclein is able to bind to DAT similar to wild type; however, the A53T mutation of a-synuclein results in an inhibition of the interaction with DAT (49). Through its ability to regulate the trafficking of DAT to the membrane, a-synuclein may function as a regulator of dopamine toxicity by regulating the amount of dopamine entering the cell. a-Synuclein has also been shown to inhibit dopamine biosynthesis by reducing tyrosine hydroxylase activity (50).

Both a- and ft-synuclein have been shown to be potent inhibitors of phospholipase D2 (PLD2) in vitro (51). PLD2 catalyzes the hydrolysis of phospha-tidylcholine into phosphatidic acid and choline (52). Because of its ability to bind to acidic phospholipids, it is possible that a-synuclein is concentrated to areas containing high levels of phosphatidic acid and then is able to inhibit PLD2, resulting in negative feedback on phosphatidic acid production. Phosphatidic acid has been proposed to be involved in kinase activation (53), regulation of GTP binding proteins (54), actin stress fibre formation (55), and regulation of vesicle formation in the trans-golgi network (56,57). a-Synuclein also shares homology with the 143-3 family of cytoplasmic chaperones, and is able to bind to 14-3-3 proteins and 14-3-3 ligands (58). 14-3-3 proteins are able to bind to and stabilize an inactive form of protein kinase C (PKC), inhibiting PKC enzymatic activity (59). Some evidence indicates that a-synuclein shares a similar ability to inhibit PKC (58). Recent studies have suggested that a-synuclein may be involved in regulation of the enzyme phospholipase Cft2, an enzyme involved in the phosphatidylinositol signaling pathway. Regulation of phospholipase Cft2 by a-synuclein is disrupted by the A53T mutation (60).

Despite these observations, the normal function of a-synuclein and its relation to the pathogenesis of PD and related a-synucleinopathies remain unclear, but further study of the function of a-synuclein may lead to insights into the pathogenesis of these disorders. However, it is clear that the polymerization of a-synuclein plays an important role in neurodegeneration in PD.

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