alpha-synuclein and Parkinson's disease: the first roadblock.
alpha-synuclein gene mutations are major underlying genetic defects known in familial juvenile onset Parkinson's disease (PD), and alpha-synuclein is a major constituent of Lewy Bodies, the pathological hallmark of PD. The normal cellular function of alpha-synuclein has been elusive, and its exact etiological mechanism in causing dopaminergic neuronal death in PD is also not clearly understood. Very recent reports now indicate that mutant or simply over-expressed alpha- synuclein could cause damage by interfering with particular steps of neuronal membrane traffic. alpha-synuclein selectively blocks endoplamic reticulum-to-Golgi transport, thus causing ER stress. A screen in a yeast revealed that alpha- synuclein toxicity could be suppressed by over-expression of the small GTPase Ypt1/Rab1, and that over-expression of the latter rescues neuron loss in invertebrate and mammalian models of alpha-synuclein-induced neurodegeneration. alpha-synuclein may also serve a chaperone function for the proper folding of synaptic SNAREs that are important for neurotransmitter release. We discuss these recent results and the emerging pathophysiological interaction of alpha-synuclein with components of neuronal membrane traffic.
Chua
Christelle En Lin
CE
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Tang
Bor Luen
BL
D000818:Animals; D004298:Dopamine / Q000378:metabolism; D006801:Humans; D016631:Lewy Bodies / Q000378:metabolism; D009154:Mutation; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D020734:Parkinsonian Disorders / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017510:Protein Folding; D021381:Protein Transport; D050600:SNARE Proteins / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D013569:Synapses / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D020761:rab1 GTP-Binding Proteins / Q000378:metabolism
D050600:SNARE Proteins; D029701:Saccharomyces cerevisiae Proteins; D051844:alpha-Synuclein; C060755:YPT1 protein, S cerevisiae; D020691:rab GTP-Binding Proteins; D020761:rab1 GTP-Binding Proteins; D004298:Dopamine