In contrast to the dominant toxic gain-of-function of a-synuclein mutations, at least three of the six known genes associated with heritable forms of PD appear to involve loss-of-function mutations (Table 1). Insight into the mechanisms by which these loss-of-function mutations cause PD will require detailed knowledge of the biological functions of the corresponding genes and the pathways regulated by these genes. One of the most powerful approaches to address these issues involves the use of classical genetic analysis in a simple model organism such as Drosophila to explore the biological functions of evolutionarily conserved homologs of these genes. This approach has recently been used to analyze the biological functions of Drosophila PARKIN, DJ-1, and PINK1 homologs.
To explore the biological role of PARKIN, we and others generated a series of mutations in the Drosophila ortholog of PARKIN, including deletion, nonsense, and missense mutations. Flies lacking the PARKIN gene are semiviable and display reduced longevity, motor deficits, and male sterility (60,61). The motor deficit of PARKIN mutants is associated with a dramatic and widespread apoptotic degeneration of muscle tissue, and the male-sterility derives from a late defect in spermatid formation in the germline. Ultrastructural studies indicate that mitochondrial dysfunction is the earliest manifestation of muscle degeneration in PARKIN mutants, suggesting a role for PARKIN in mitochondrial integrity (60). This conclusion is further underscored by the finding that late spermatids in PARKIN mutants manifest dramatic structural alterations in the mitochondrial derivatives known as Nebenkern that are responsible for the energy production required for sperm motility (62). While humans and mice with PARKIN mutations do not appear to manifest similar muscle and germline phenotypes, mitochondrial defects are a common characteristic of sporadic PD and a conserved feature in all organisms with PARKIN mutations, including humans (63,64). These observations suggest that PARKIN may act, either directly or indirectly, to regulate mitochondrial integrity and that mitochondrial dysfunction is a triggering feature of dopamine neuron death in humans lacking PARKIN function. The mitochondrial dysfunction observed in PARKIN mutants may also explain the reported sensitivity of mutant flies to oxidative stress inducing agents (61). However, our unpublished work indicates that PARKIN mutants are
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