Mutations in DJ-1 (PARK7) are a known cause of early-onset autosomal recessive Parkinson's disease (PD). Accumulating evidence indicates that abnormalities of synaptic vesicle trafficking underlie the pathophysiological mechanism of PD. In the present study, we explored whether DJ-1 is involved in CNS synaptic function. DJ-1 deficiency impaired synaptic vesicle endocytosis and reavailability without inducing structural alterations in synapses. Familial mutants of DJ-1 (M26I, E64D, and L166P) were unable to rescue defective endocytosis of synaptic vesicles, whereas WT DJ-1 expression completely restored endocytic function in DJ-1 KO neurons. The defective synaptic endocytosis shown in DJ-1 KO neurons may be attributable to alterations in membrane cholesterol level. Thus, DJ-1 appears essential for synaptic vesicle endocytosis and reavailability, and impairment of this function by familial mutants of DJ-1 may be related to the pathogenesis of PD.
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