Snaring the Function of α-Synuclein

It is well established that the abundant neuronal protein ␣-synuclein has a causal role in Parkinson's disease , yet the normal functions of this protein remain unclear. In this issue of Cell, Chandra et al. (2005) reveal that ␣-synuclein acts as a molecular chaperone, assisting in the folding and refolding of synaptic proteins called SNAREs. These proteins are crucial for release of neurotransmitters at the neuronal synapse, vesicle recycling, and synaptic integrity. The synucleins are abundant proteins that are predominantly expressed in neurons throughout the mammalian nervous system. They are characterized by their relatively small size (127–140 amino acids) and highly The two major synuclein proteins expressed in the central nervous system—α-synuclein and β-synuclein—are localized predominantly in presynaptic nerve terminals. Although they have been implicated in many cellular activities, the exact physiological function of synucleins has been difficult to pin down. Notably, synucleins are unfolded in solution, but the addition of phospholipids induces α-synuclein to acquire an amphipathic α-helical structure that facilitates interactions with synthetic lipid vesi-cles. Synucleins can also act as ATP-independent molecular chaperones in vitro, preventing the aggregation of denatured proteins. The discovery that a point mutation (A53T) in the α-synuclein gene (SNCA) can cause autosomal dominant Parkinson's disease (PD), a neurodegenerative motor disorder, has generated much interest in the sy-nucleins (Cookson, 2005; Dawson and Dawson, 2003). Subsequently, additional mutations (A30P and E46K) in α-synuclein, including duplications and trisomies of the SNCA genomic region, have been identified. Furthermore , α-synuclein is the major component of fibrillar cellular inclusions called Lewy bodies, a pathological hallmark of PD. Indeed, abnormal accumulation of α-synuclein in Lewy bodies and other types of pathological inclusions is associated with an entire spectrum of neurodegenerative diseases in addition to PD, collectively termed the synucleinopathies. Many pathological and experimental findings support the notion that formation of α-synuclein inclusions may lead to dysfunction of neurons and their degeneration due to the obstruction of normal cellular trafficking and/ or the trapping of cellular components in inappropriate In addition, small oligomers of α-synuclein may be toxic, and these different mechanisms of cellular dysfunction are not mutually exclusive. The A53T and E46K mutations in α-synuclein may cause disease by increasing the propensity of α-synuclein to form fibrils and inclusions. Given that the polymeriza-tion of α-synuclein into fibrils is concentration dependent , genetic aberrations that increase the copy number of the gene are likely to cause disease due to the increased …