Prime time for α-synuclein

AD Gitler, J Shorter - Journal of Neuroscience, 2007 - Soc Neuroscience
Journal of Neuroscience, 2007Soc Neuroscience
Parkinson's disease (PD) is the most common neurodegenerative movement disorder,
afflicting1% of individuals over the age of 65. PD results primarily from a severe and
selective devastation of dopaminergic neurons in the substantia nigra pars compacta,
although neuropathology extends to other brain regions. Overwhelming evidence implicates
the presynaptic protein α-synuclein (α-syn) in the pathogenesis of PD. α-Syn is a major
constituent of Lewy Bodies, cellular inclusions that are the pathological hallmark of PD …
Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, afflicting1% of individuals over the age of 65. PD results primarily from a severe and selective devastation of dopaminergic neurons in the substantia nigra pars compacta, although neuropathology extends to other brain regions. Overwhelming evidence implicates the presynaptic protein α-synuclein (α-syn) in the pathogenesis of PD. α-Syn is a major constituent of Lewy Bodies, cellular inclusions that are the pathological hallmark of PD. Furthermore, several missense mutations in the α-syn gene and duplication or triplication of the wild-type locus are linked with early-onset PD in rare familial forms of the disease. Overexpression of α-syn, or PD-associated α-syn mutants, in mouse, rat, fly, worm, and even yeast suggest that excess accumulation of α-syn leads to cellular toxicity (Moore et al., 2005; Lee and Trojanowski, 2006). Despite intense study, the precise function of α-syn remains unresolved. However, a growing body of evidence suggests a role in the maintenance of synaptic vesicle pools (Murphy et al., 2000; Cabin et al., 2002), activity-dependent dopamine release (Abeliovich et al., 2000), or as an auxiliary chaperone for the assembly of specific soluble N-ethylmaleimidesensitive factor attached protein receptor (SNARE) complexes that drive vesicle fusion with the plasma membrane (Chandra et al., 2005). Despite these indications, single and double knock-outs of α-, ß-, and-synuclein are viable and exhibit very little (if any) phenotype under basal conditions (Chandra et al., 2004). However, synucleins may perform subtle regulatory functions and might even become essential under specific situations of stress or injury. Indeed, an essential function for α-syn has been revealed in cysteine-string protein-α-deficient mice (Chandra et al., 2005).
Soc Neuroscience