Mice Lacking α-Synuclein Display Functional Deficits in the Nigrostriatal Dopamine System

The subcellular localization 46100 Burjasot of the synucleins has not been established definitively, Spain and suggested sites of action include the presynaptic 3 Although its physiological activity remains unclear, Summary ␣-Syn has been implicated in the etiology of two common neurodegenerative disorders, Alzheimer's disease ␣-Synuclein (␣-Syn) is a 14 kDa protein of unknown (AD) and Parkinson's disease (PD). The pathological function that has been implicated in the pathophysiol-hallmark of AD involves widespread depositions (termed ogy of Parkinson's disease (PD). Here, we show that amyloid plaques) of a 42 amino acid ␤-amyloid peptide ␣-Syn Ϫ/Ϫ mice are viable and fertile, exhibit intact brain (A␤) concomitant with the degeneration of hippocampal architecture, and possess a normal complement of and cortical neurons. The cause of A␤ depositions is dopaminergic cell bodies, fibers, and synapses. Nigro-not fully understood. However, a fragment of ␣-Syn striatal terminals of ␣-Syn Ϫ/Ϫ mice display a standard termed the nonamyloid component (NAC; Ueda et al., pattern of dopamine (DA) discharge and reuptake in 1993) was found to be an integral constituent of these response to simple electrical stimulation. However, plaques in the AD brain. Moreover, NAC binds to they exhibit an increased release with paired stimuli ␤-amyloid peptide in vitro and facilitates its aggregation that can be mimicked by elevated Ca 2؉ ., raising the with the altered DA release, ␣-Syn Ϫ/Ϫ mice display a possibility that NAC facilitates plaque formation and the reduction in striatal DA and an attenuation of DA-progression of AD. dependent locomotor response to amphetamine. These PD brain pathology is typified by the presence of ab-findings support the hypothesis that ␣-Syn is an essen-normal protein aggregates, termed Lewy bodies, and tial presynaptic, activity-dependent negative regulator selective loss of dopamine (DA) neurons. ␣-Syn appears of DA neurotransmission. to be the major protein component of these intracy-toplasmic deposits in sporadic and familial forms of the disease (Mezey et al., 1998; Spillantini et al., 1998). Direct Introduction evidence for the involvement of ␣-Syn in PD was provided by genetic studies of patients with rare, domi-␣-Synuclein (␣-Syn) was initially isolated from choliner-nantly inherited variants of this disorder. Two indepen-gic nerve terminals of the Torpedo ray electric organ dent pathological mutations have been described, a (Maroteaux et al., 1988). Mammalian ␣-Syn was subse-change from alanine to threonine at position 53 in Italian-quently found to be prominently expressed in regions American and Greek families (Polymeropoulos et al., 1997) and a change …