Article

Drosophila PINK1 is required for mitochondrial function and interacts genetically with Parkin

Nature (Impact Factor: 41.46). 05/2006; 441(7097):1162-1166. DOI: 10.1038/nature04779
Source: PubMed

ABSTRACT

Parkinson's disease is the second most common neurodegenerative disorder and is characterized by the degeneration of dopaminergic neurons in the substantia nigra. Mitochondrial dysfunction has been implicated as an important trigger for Parkinson's disease-like pathogenesis because exposure to environmental mitochondrial toxins leads to Parkinson's disease-like pathology

    • "In addition, after 25 mM DTT treatment, 0% of bees survive for 3 days. By contrast, in fruit flies this same dose results in survival of nearly 100% for longer than 6 days (Park et al., 2011) and evidence exists that fruit flies survive at considerably higher doses (Clark et al., 2006). While the mechanistic basis for differences in response to environmental stresses between species is incompletely understood, a few possible explanations can be offered for these observed differences . "
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    ABSTRACT: Honey bee colonies in the United States have suffered from an increased rate of die-off in recent years, stemming from a complex set of interacting stresses that remain poorly described. While we have some understanding of the physiological stress responses in the honey bee, our molecular understanding of honey bee cellular stress responses is incomplete. Thus, we sought to identify and began functional characterization of the components of the UPR in honey bees. The IRE1-dependent splicing of the mRNA for the transcription factor Xbp1, leading to translation of an isoform with more transactivation potential, represents the most conserved of the UPR pathways. Honey bees and other Apoidea possess unique features in the Xbp1 mRNA splice site, which we reasoned could have functional consequences for the IRE1 pathway. However, we find robust induction of target genes upon UPR stimulation. In addition, the IRE1 pathway activation, as assessed by splicing of Xbp1 mRNA upon UPR, is conserved. By providing foundational knowledge about the UPR in the honey bee and the relative sensitivity of this species to divergent stresses, this work stands to improve our understanding of the mechanistic underpinnings of honey bee health and disease.
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    • "Another important gene identified in familial PD is PINK-1 which encodes a mitochondrial-targeting serine/threonine kinase. PINK-1 mutations cause severe multi-system mitochondrial impairment (e.g., disruption of mitochondrial morphology causing a fragmented mitochondria appearance (Clark et al., 2006;Exner et al., 2007)) which is rescued by Parkin overexpression, suggesting PINK-1 acts upstream of Parkin (Clark et al., 2006). The final protein in the triad, DJ-1 is another gene which is reported to have a mitochondrial function in scavenging reactive oxygen species (ROS) (Canet-Avil es et al., 2004;Taira et al., 2004). "
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    ABSTRACT: Increasingly in the realm of neurological disorders, particularly those involving neurodegeneration, mitochondrial dysfunction is emerging at the core of their pathogenic processes. Most of these diseases still lack effective treatment and are hampered by a shortfall in the development of novel medicines. Clearly new targets that translate well to the clinic are required. Physiological parameters in the form of neuronal network activity are increasingly being used as a therapeutic screening approach in drug development and disorders with mitochondrial dysfunction generally display neuronal network activity disturbance. However research directly linking the disturbances in neuronal network activity with mitochondrial dysfunction is only just starting to emerge. This review will summarize the breadth of knowledge linking neuronal network activity to mitochondrial dysfunction in neurodegenerative diseases and suggest potential avenues for exploration in respect to future drug development.
    Full-text · Article · Oct 2015 · Neuropharmacology
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    • "Loss of PINK1 or parkin function results in mitochondrial dysfunction (Schapira and Gegg 2011). Initial work with PINK1 and parkin in Drosophila models suggested that these proteins function in the same signalling pathway to maintain mitochondrial function (Clark et al. 2006;Park et al. 2006). Consequently, it has been shown that in mammalian cells, chemical induction ofReceivedGCase, glucocerebrosidase; HEX, b-hexosaminidase; KD, knockdown; KO, knockout; MEFs, mouse embryonic fibroblasts; MFN, mitofusin; NQO1, NAD(P)H dehydrogenase quinone 1; OMM, outer mitochondrial membrane; PBS, phosphate buffered saline; PD, Parkinson's disease; TFEB, transcription factor EB. mitophagy by use of the uncoupler carbonyl cyanide m-chlorophenylhydrazone (CCCP) causes stabilisation of PINK1 on the outer mitochondrial membrane. "
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    ABSTRACT: Impairment of the autophagy-lysosome pathway (ALP) is implicated with the changes in α-synuclein and mitochondrial dysfunction observed in Parkinson's disease (PD). Damaged mitochondria accumulate PINK1, which then recruits parkin, resultingin ubiquitination of mitochondrial proteins. These can then be bound by the autophagic proteins p62/SQSTM1 and LC3, resulting in degradation of mitochondria by mitophagy. Mutations in PINK1 and parkin genes are a cause of familial PD. We found a significant increase in the expression of p62/SQSTM1 mRNA and protein following mitophagy induction in human neuroblastoma SH-SY5Y cells. p62 protein not only accumulated on mitochondria, but was also greatly increased in the cytosol. Increased p62/SQSMT1 expression was prevented in PINK1 knock down (KD) cells, suggesting increased p62 expression was a consequence of mitophagy induction. The transcription factors Nrf2 and TFEB, which play roles in mitochondrial and lysosomal biogenesis, respectively, can regulate p62/SQSMT1. We report that both Nrf2 and TFEB translocate to the nucleus following mitophagy induction and that the increase in p62 mRNA levels was significantly impaired in cells with Nrf2 or TFEB KD.. TFEB translocation also increased expression of itself and lysosomal proteins such as glucocerebrosidase and cathepsin D following mitophagy induction. We also report that cells with increased TFEB protein have significantly higher PGC-1α mRNA levels, a regulator of mitochondrial biogenesis, resulting in increased mitochondrial content. Our data suggests that TFEB is activated following mitophagy to maintain ALP and mitochondrial biogenesis. Therefore strategies to increase TFEB may improve both the clearance of α-synuclein and mitochondrial dysfunction in PD. This article is protected by copyright. All rights reserved.
    Full-text · Article · Oct 2015 · Journal of Neurochemistry
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