Mutations in the parkin gene are thought to cause a loss of ligase function preventing the ubiquitination of its substrates. This supported the hypothesis of impaired ubiquitin-mediated protein degradation causing neurodegeneration in PD via accumulation of Parkin substrates. However, existing loss-of-function mouse models do not display any neuronal loss and do not exhibit an accumulation of any of the known Parkin substrates (Itier et al., 2003; Palacino et al., 2004; Goldberg et al., 2003). An interesting feature in parkin knockout mice was an effect on mitochon-drial respiratory capacity and indirect markers for oxidative stress (Palacino et al., 2004). Mitochondrial dysfunction is a common feature of PD (Beal, 2000). A specific and selective loss of mitochondrial complex I activity in the substantia nigra of PD patients reflects an important mechanism of mitochondrial pathology in PD (Shapira, 1999). Neuronal mitochondria function as integrators of diverse cellular stresses and mediators of apoptosis and therefore represent a major interface between endogenous or exogenous toxins and neurodegeneration. Mitochondrial dysfunction was also observed in a parkin knockout Drosophila model displaying morphologically altered mitochondria and increased susceptibility to oxidative stress (Pesah et al., 2004; Greene et al., 2003). These observations concerning mitochondrial dysfunction might further link Parkin to the other genes identified in autosomal recessive PD.
One of these, PINK1, encodes a serine/ threonine kinase that is induced by PTEN in response to oxidative stress. The protein is encoded in the nucleus and translocated from the cytoplasm to the mitochondria to exert its physiological function. Overexpression of G30D mutant PINK1 significantly reduced cell viability in the paradigm of proteasome inhibitor MG132-induced cellular stress in vitro, suggesting an important protective function of the wild type protein in mitochondria (Valente et al., 2004). Another functional study on two point mutations (G309D and L347P) revealed a loss of kinase activity as a possible pathogenic mechanism (Beilina et al., 2005). A recent study indicated that a substantial portion of the PINK1 protein may be exported to the cytosol after mitochondrial processing. Moreover, overexpression of PINK1 in cell culture led to intracytoplasmic inclusions reminiscent of insoluble aggregating proteins, which might indicate a contribution of disturbed protein degradation to the pathogenic mechanism (Beilina et al., 2005). Future studies will unravel the substrates of PINK1 in mitochondria and in the cytosol and how PINK1 may interfere with mito-chondrial homeostasis and/or the ubiquitin proteasome system.
The most interesting feature of DJ-1 that is mutated in another form of autosomal recessive PD is its function as a sensor of oxi-dative stress. Under oxidative conditions, an acidic form of the DJ-1 protein accumulates and mediates its translocation to the mitochondria in vitro (Canet-Aviles et al., 2004). Indeed, a protective function of DJ-1 in terms of oxidative stress and inhibition of mito-chondrial complex I activity has been shown (Taira et al., 2004). In this context, the oxi-dative modification of the sulfhydryl group of cystein in position 106 of the peptide sequence seems to be critical, since a mutation of this amino acid leads to a dominant negative effect in the paradigm of mitochondrial damage (Canet-Aviles et al., 2004). Therefore, loss of function mutations in the DJ-1 gene, as suggested from the autosomal recessive mode of inheritance, might lead to increased susceptibility to oxidative stress conditions.
Recently, another genetic susceptibility factor was described that links mitochondrial pathology with PD. Omi/HtrA2 is a nuclear encoded mitochondrial protein involved in cellular stress response and mitochondrial homeostasis. In German PD patients, two novel variants of the Omi/HtrA2 protein were identified that result in defective activation of the protease activity of Omi/HtrA2. Immunohis-tochemistry and functional analysis in stably transfected cells revealed that S399 mutant Omi/HtrA2 and to a lesser extent the risk allele of the A141S polymorphism induced mitochondrial dysfunction associated with altered mitochondrial morphology. Cells over-expressing S399 mutant Omi/HtrA2 were more susceptible to stress-induced cell death than wild type expressing cells (Strauss et al., 2005).
In summary, the functional characterization of identified genes in PD reveals mitochon-drial pathology and defective protein degradation processes. Interestingly, biochemical data and pathological studies in sporadic PD patients show that mechanisms identified in inherited forms of the disease are also involved in the pathogenesis of the common sporadic form.
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