Neuron Article Increased Expression of a-Synuclein Reduces Neurotransmitter Release by Inhibiting Synaptic Vesicle Reclustering after Endocytosis Venu M. Nemani,1 Wei Lu,2 Victoria Berge,3 Ken Nakamura,1 Bibiana Onoa,1 Michael K. Lee,4 Farrukh A. Chaudhry,3 Roger A. Nicoll,2 and Robert H. Edwards1,* 1Departments of Neurology and Physiology, Graduate Program in Neuroscience 2Department of Cellular and Molecular Pharmacology University of California, San Francisco, San Francisco, CA 94158, USA 3The Biotechnology Centre of Oslo, Centre for Molecular Biology and Neuroscience, University of Oslo, Oslo, Norway 4Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA *Correspondence:
[email protected] DOI 10.1016/j.neuron.2009.12.023 SUMMARY Parkinson’s disease (PD) and Lewy body dementia (LBD) (Spill- antini et al., 1998; Dickson, 2001). Point mutations in asyn are The protein a-synuclein accumulates in the brain of also linked to an autosomal-dominant form of PD (Polymeropou- patients with sporadic Parkinson’s disease (PD), los et al., 1997; Kru¨ ger et al., 1998; Zarranz et al., 2004). Taken and increased gene dosage causes a severe, domi- together, these observations suggest a causative role for asyn nantly inherited form of PD, but we know little about in sporadic as well as inherited PD and LBD. In addition, duplica- the effects of synuclein that precede degeneration. tion and triplication of the asyn gene suffice to cause a severe, a-Synuclein localizes to the nerve terminal, but the highly penetrant form of PD (Singleton et al., 2003; Chartier- Harlin et al., 2004), and polymorphisms in regulatory elements knockout has little if any effect on synaptic transmis- of the asyn gene predispose to PD (Maraganore et al., 2006), sion.