Physiology and pathophysiology of alpha-synuclein - Cell culture and transgenic animal models based on a Parkinson's disease-associated protein

Abstract

The 15-20 kDa synuclein (SYN) phosphoproteins are abundantly expressed in nervous tissue. Members of the family include alpha- and beta -SYN, and the more distantly related gamma -SYN and synoretin. SYN genes have been identified in Torpedo, canary, and several mammalian species, indicating an evolutionary conserved role. Expression of alpha -SYN was found to be modulated in situations of neuronal remodeling, namely, songbird learning and after target ablation of dopaminergic striatonigral neurons in the rat. The presynaptic localization of alpha -SYN is further supportive of a direct physiological role in neuronal plasticity. The extensive synaptic co-localization of alpha- and beta -SYN might indicate functional redundancy of these highly homologous synucleins. However, alpha -SYN was the only family member identified in Lewy bodies and cytoplasmic inclusions characteristic for multiple system atrophy. Moreover, alpha -SYN was genetically linked to familial Parkinson's disease. The two Parkinson's disease-associated mutations accelerated the intrinsic aggregation property of alpha -SYN in vitro. Post-translational modifications, such as phosphorylation and proteolysis, and/or interaction with other proteins, might regulate alpha -SYN fibril formation in vivo. Cytoskeletal elements and signal transduction intermediates have been recently identified as binding partners for alpha -SYN. Preliminary data available from transgenic mice suggest that (over)expressed human alpha -SYN proteins are less efficiently cleared from the neuronal cytosol. Thus, Parkinson's disease-associated mutations might perturb axonal transport, leading to somal accumulation of alpha -SYN and eventually Lewy body formation.