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 ex...

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Bibliographic Details
Published in:Journal of cellular and molecular medicine 2006-10, Vol.10 (4), p.837-846
Main Authors: Chua, Christelle En Lin, Tang, Bor Luen
Format: Article
Language:English
Subjects:
alpha-Synuclein - genetics
alpha-Synuclein - metabolism
Animals
Dopamine - metabolism
Humans
Lewy Bodies - metabolism
Mutation
Neurons - metabolism
Neurons - pathology
Parkinsonian Disorders - genetics
Parkinsonian Disorders - metabolism
Parkinsonian Disorders - pathology
Protein Folding
Protein Transport
rab GTP-Binding Proteins - metabolism
rab1 GTP-Binding Proteins - metabolism
Saccharomyces cerevisiae - metabolism
Saccharomyces cerevisiae Proteins - metabolism
SNARE Proteins - metabolism
Synapses - metabolism
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Summary: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.
ISSN:1582-1838
1582-4934
DOI:10.1111/j.1582-4934.2006.tb00528.x