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      Reduction of Protein Translation and Activation of Autophagy Protect against PINK1 Pathogenesis in Drosophila melanogaster

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      PLoS Genetics
      Public Library of Science

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          Abstract

          Mutations in PINK1 and Parkin cause familial, early onset Parkinson's disease. In Drosophila melanogaster, PINK1 and Parkin mutants show similar phenotypes, such as swollen and dysfunctional mitochondria, muscle degeneration, energy depletion, and dopaminergic (DA) neuron loss. We previously showed that PINK1 and Parkin genetically interact with the mitochondrial fusion/fission pathway, and PINK1 and Parkin were recently proposed to form a mitochondrial quality control system that involves mitophagy. However, the in vivo relationships among PINK1/Parkin function, mitochondrial fission/fusion, and autophagy remain unclear; and other cellular events critical for PINK1 pathogenesis remain to be identified. Here we show that PINK1 genetically interacted with the protein translation pathway. Enhanced translation through S6K activation significantly exacerbated PINK1 mutant phenotypes, whereas reduction of translation showed suppression. Induction of autophagy by Atg1 overexpression also rescued PINK1 mutant phenotypes, even in the presence of activated S6K. Downregulation of translation and activation of autophagy were already manifested in PINK1 mutant, suggesting that they represent compensatory cellular responses to mitochondrial dysfunction caused by PINK1 inactivation, presumably serving to conserve energy. Interestingly, the enhanced PINK1 mutant phenotype in the presence of activated S6K could be fully rescued by Parkin, apparently in an autophagy-independent manner. Our results reveal complex cellular responses to PINK1 inactivation and suggest novel therapeutic strategies through manipulation of the compensatory responses.

          Author Summary

          Parkinson's disease is the most common neurodegenerative disease affecting the aging population. Clinically it manifests as tremor, muscle rigidity, slow movement, and postural instability. Parkinson's disease is a chronic disorder, and its occurrence and progression are determined by genetic backgrounds and environmental factors. Although the most common forms of Parkinson's disease, the so-called “idiopathic” forms, generally affect people older than 50, some familial forms of the disease occur before age 40. Mutations in PINK1 and Parkin genes have been associated with the latter forms of Parkinson's disease. The inactivation of PINK1 or Parkin causes dysfunction of mitochondria, the powerhouse of the cell, leading to the degeneration of tissues such as the brain and muscle that have high energy demand. In an effort to understand how genetic mutations in PINK1 result in disease and to find effective ways to intervene, we have performed genetic studies in the model organism Drosophila melanogaster and found that reduced protein translation or increased autophagy can efficiently mitigate the phenotypes caused by PINK1 inactivation. Our result suggests that pharmacological manipulations of these newly identified PINK1-interacting pathways may prove beneficial for the treatment of Parkinson's disease.

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          Most cited references24

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          AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy.

          D Hardie (2007)
          The SNF1/AMP-activated protein kinase (AMPK) family maintains the balance between ATP production and consumption in all eukaryotic cells. The kinases are heterotrimers that comprise a catalytic subunit and regulatory subunits that sense cellular energy levels. When energy status is compromised, the system activates catabolic pathways and switches off protein, carbohydrate and lipid biosynthesis, as well as cell growth and proliferation. Surprisingly, recent results indicate that the AMPK system is also important in functions that go beyond the regulation of energy homeostasis, such as the maintenance of cell polarity in epithelial cells.
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            Dynamics and diversity in autophagy mechanisms: lessons from yeast.

            Autophagy is a fundamental function of eukaryotic cells and is well conserved from yeast to humans. The most remarkable feature of autophagy is the synthesis of double membrane-bound compartments that sequester materials to be degraded in lytic compartments, a process that seems to be mechanistically distinct from conventional membrane traffic. The discovery of autophagy in yeast and the genetic tractability of this organism have allowed us to identify genes that are responsible for this process, which has led to the explosive growth of this research field seen today. Analyses of autophagy-related (Atg) proteins have unveiled dynamic and diverse aspects of mechanisms that underlie membrane formation during autophagy.
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              Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway.

              In many species, reducing nutrient intake without causing malnutrition extends lifespan. Like DR (dietary restriction), modulation of genes in the insulin-signaling pathway, known to alter nutrient sensing, has been shown to extend lifespan in various species. In Drosophila, the target of rapamycin (TOR) and the insulin pathways have emerged as major regulators of growth and size. Hence we examined the role of TOR pathway genes in regulating lifespan by using Drosophila. We show that inhibition of TOR signaling pathway by alteration of the expression of genes in this nutrient-sensing pathway, which is conserved from yeast to human, extends lifespan in a manner that may overlap with known effects of dietary restriction on longevity. In Drosophila, TSC1 and TSC2 (tuberous sclerosis complex genes 1 and 2) act together to inhibit TOR (target of rapamycin), which mediates a signaling pathway that couples amino acid availability to S6 kinase, translation initiation, and growth. We find that overexpression of dTsc1, dTsc2, or dominant-negative forms of dTOR or dS6K all cause lifespan extension. Modulation of expression in the fat is sufficient for the lifespan-extension effects. The lifespan extensions are dependent on nutritional condition, suggesting a possible link between the TOR pathway and dietary restriction.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                1553-7390
                1553-7404
                December 2010
                December 2010
                9 December 2010
                : 6
                : 12
                : e1001237
                Affiliations
                [1]Department of Pathology, Stanford University School of Medicine, Stanford, California, United States of America
                University of Minnesota, United States of America
                Author notes

                Conceived and designed the experiments: SL BL. Performed the experiments: SL. Analyzed the data: SL BL. Wrote the paper: SL BL.

                Article
                10-PLGE-RA-3882R2
                10.1371/journal.pgen.1001237
                3000346
                21151574
                f5d0ba8b-4802-4d3c-8c39-d62654d616f6
                Liu, Lu. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 11 August 2010
                : 3 November 2010
                Page count
                Pages: 12
                Categories
                Research Article
                Neurological Disorders

                Genetics
                Genetics

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