he incidence of many common diseases is increased among the relatives of affected patients, but the pattern of inheritance rarely follows Mendel's laws. Instead, such common diseases are thought to result from a complex interaction among multiple predisposing genes and other factors, including environmental contributions and chance occurrences. Identifying the genetic contribution to such complex diseases is a major challenge for genomic medicine. However, as so clearly foreseen nearly 350 years ago by the English physiologist William Harvey, 1 finding the genetic basis for rarer, mendelian forms of a disease may illuminate the etiologic process and pathogenesis of the more common, complex forms. This is illustrated in the progress made in understanding Alzheimer's disease and Parkinson's disease through the investigation of the rare, clearly inherited forms of these diseases. The molecular basis of neurodegenerative disorders was reviewed in the

Although the mutation of alpha-synuclein, a protein associated with presynaptic vesicles, is implicated in the etiology and pathogenesis of Parkinson's disease, the biological function of the normal protein is unknown. Mice that lack alpha-synuclein have been generated by homologous recombination in embryonic stem cells. Electron microscopic examination of hippocampal synapses revealed a striking selective deficiency of undocked vesicles without affecting docked vesicles. Field recording of CA1 synapses in hippocampal slices from the mutant mice demonstrated normal basal synaptic transmission, paired-pulse facilitation, and response to a brief train of high-frequency stimulation (100 Hz, 40 pulses) that exhausts only docked vesicles. In contrast, the alpha-synuclein knock-out mice exhibited significant impairments in synaptic response to a prolonged train of repetitive stimulation (12.5 Hz, 300 pulses) capable of depleting docked as well as reserve pool vesicles. Moreover, the replenishment of the docked vesicles by reserve pool vesicles after depletion was slower in the mutant synapses. Thus, alpha-synuclein may be required for the genesis and/or maintenance of a subset of presynaptic vesicles, those in the "reserve" or "resting" pools. These results reveal, for the first time, the normal function of endogenous alpha-synuclein in regulating synaptic vesicle mobilization at nerve terminals.

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