Loss of the E3 ubiquitin ligase Parkin causes early onset Parkinson's disease, a neurodegenerative disorder of unknown etiology. Parkin has been linked to multiple cellular processes including protein degradation, mitochondrial homeostasis, and autophagy; however, its precise role in pathogenesis is unclear. Recent evidence suggests that Parkin is recruited to damaged mitochondria, possibly affecting mitochondrial fission and/or fusion, to mediate their autophagic turnover. The precise mechanism of recruitment and the ubiquitination target are unclear. Here we show in Drosophila cells that PINK1 is required to recruit Parkin to dysfunctional mitochondria and promote their degradation. Furthermore, PINK1 and Parkin mediate the ubiquitination of the profusion factor Mfn on the outer surface of mitochondria. Loss of Drosophila PINK1 or parkin causes an increase in Mfn abundance in vivo and concomitant elongation of mitochondria. These findings provide a molecular mechanism by which the PINK1/Parkin pathway affects mitochondrial fission/fusion as suggested by previous genetic interaction studies. We hypothesize that Mfn ubiquitination may provide a mechanism by which terminally damaged mitochondria are labeled and sequestered for degradation by autophagy.is a common neurodegenerative disorder principally affecting the degeneration of nigral dopaminergic neurons. The pathogenic mechanisms are unknown, but valuable insight has been gained from identifying gene mutations causative for familial forms of PD (1). Loss-of-function mutations in PINK1 and parkin are the major cause of autosomal recessive, early onset PD. PINK1 encodes a mitochondria-targeted kinase (2) whereas parkin encodes an E3 ubiquitin ligase (3), a class of enzymes that conjugate ubiquitin to target substrates. This modification is usually considered in the context of substrate degradation by the proteasome, but ubiquitination also serves many other cellular functions. Consequently, much emphasis has been put on elucidating a link between Parkin dysfunction and protein aggregation. Despite the identification of numerous putative Parkin substrates, an unequivocal causative link between substrate aggregation and pathogenesis remains debatable.There is strong evidence, however, that supports an important role for Parkin in regulating mitochondrial homeostasis (4). Studies have revealed a conserved function of Parkin acting downstream of PINK1 to protect mitochondrial integrity and prevent oxidative stress-induced apoptosis (5-8). Recently, we and others have reported that Drosophila parkin and PINK1 genetically interact with components of the mitochondrial fission and fusion machinery (9-12), suggesting that loss of PINK1/parkin function may lead to excess mitochondrial fusion. Consistent with this, mitochondrial elongation has been reported in cells derived from PD patients with parkin mutations (13). However, the effects of parkin or PINK1 deficiency in mammalian cells remain unresolved because additional reports describe inconsistent phenotypes in PINK...
Mutations in PINK1 and parkin cause autosomal recessive parkinsonism, a neurodegenerative disorder characterized by the loss of dopaminergic neurons. To highlight potential therapeutic pathways we have identified factors that genetically interact with parkin/PINK1. Here we report that overexpression of the translation inhibitor 4E-BP can suppress all pathologic phenotypes including degeneration of dopaminergic neurons in Drosophila. 4E-BP is activated in vivo by the TOR inhibitor rapamycin, which we find can potently suppress pathology in PINK1/parkin mutants. Rapamycin also ameliorates mitochondrial defects in cells from parkin-mutant patients. Recently, 4E-BP was shown to be inhibited by the most common cause of parkinsonism, dominant mutations in LRRK2. Here we further show that loss of the Drosophila LRRK2 homolog activates 4E-BP and is also able to suppress PINK1/parkin pathology. Thus, in conjunction with recent findings our results suggest that pharmacologic stimulation of 4E-BP activity may represent a viable therapeutic approach for multiple forms of parkinsonism.
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