Physiology and pathophysiology of alpha-synuclein. Cell culture and transgenic animal models based on a Parkinson's disease-associated protein.
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.
Kahle
P J
PJ
Adolf Butenandt Institute, Department of Biochemistry, Ludwig Maximilians University, Schillerstrasse 44, 80336 Munich, Germany. pkahle@pbm.med.uni-muenchen.de
Neumann
M
M
Ozmen
L
L
Haass
C
C
D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000473:pathology / Q000502:physiology*; D010300:Parkinson Disease / Q000235:genetics / Q000503:physiopathology*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013569:Synapses / Q000502:physiology; D051843:Synucleins; D051844:alpha-Synuclein
D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; C497605:Snca protein, mouse; D051843:Synucleins; D051844:alpha-Synuclein