title: Knockdown of Hsc70-5/mortalin induces loss of synaptic mitochondria in a Drosophila Parkinson's disease model.
abstract: Mortalin is an essential component of the molecular machinery that imports nuclear-encoded proteins into mitochondria, assists in their folding, and protects against damage upon accumulation of dysfunctional, unfolded proteins in aging mitochondria. Mortalin dysfunction associated with Parkinson's disease (PD) increases the vulnerability of cultured cells to proteolytic stress and leads to changes in mitochondrial function and morphology. To date, Drosophila melanogaster has been successfully used to investigate pathogenesis following the loss of several other PD-associated genes. We generated the first loss-of-Hsc70-5/mortalin-function Drosophila model. The reduction of Mortalin expression recapitulates some of the defects observed in the existing Drosophila PD-models, which include reduced ATP levels, abnormal wing posture, shortened life span, and reduced spontaneous locomotor and climbing ability. Dopaminergic neurons seem to be more sensitive to the loss of mortalin than other neuronal sub-types and non-neuronal tissues. The loss of synaptic mitochondria is an early pathological change that might cause later degenerative events. It precedes both behavioral abnormalities and structural changes at the neuromuscular junction (NMJ) of mortalin-knockdown larvae that exhibit increased mitochondrial fragmentation. Autophagy is concomitantly up-regulated, suggesting that mitochondria are degraded via mitophagy. Ex vivo data from human fibroblasts identifies increased mitophagy as an early pathological change that precedes apoptosis. Given the specificity of the observed defects, we are confident that the loss-of-mortalin model presented in this study will be useful for further dissection of the complex network of pathways that underlie the development of mitochondrial parkinsonism.
authors.affiliation: Junior Research Group Synaptic Plasticity, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany ; Graduate School of Cellular & Molecular Neuroscience, University of Tübingen, Tübingen, Germany.
authors.forename: Jun-Yi
authors.initials: JY
authors.lastname: Zhu
authors.affiliation: Junior Research Group Synaptic Plasticity, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
authors.forename: Natalia
authors.initials: N
authors.lastname: Vereshchagina
authors.affiliation: Junior Research Group Synaptic Plasticity, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany ; Graduate School of Cellular & Molecular Neuroscience, University of Tübingen, Tübingen, Germany ; German Center for Neurodegenerative Diseases, Tübingen, Germany.
authors.forename: Vrinda
authors.initials: V
authors.lastname: Sreekumar
authors.affiliation: German Center for Neurodegenerative Diseases, Tübingen, Germany ; Department of Neurodegenerative Diseases and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
authors.forename: Lena F
authors.initials: LF
authors.lastname: Burbulla
authors.affiliation: Cell Death Regulation Laboratory, MRC Toxicology Unit, Leicester, United Kingdom.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Costa
authors.affiliation: Junior Research Group Synaptic Plasticity, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
authors.forename: Katharina J
authors.initials: KJ
authors.lastname: Daub
authors.affiliation: Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Woitalla
authors.affiliation: Cell Death Regulation Laboratory, MRC Toxicology Unit, Leicester, United Kingdom.
authors.forename: L Miguel
authors.initials: LM
authors.lastname: Martins
authors.affiliation: German Center for Neurodegenerative Diseases, Tübingen, Germany ; Department of Neurodegenerative Diseases and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany ; Werner Reichardt Centre for Integrative Neuroscience, University of Tübingen, Tübingen, Germany.
authors.forename: Rejko
authors.initials: R
authors.lastname: Krüger
authors.affiliation: Junior Research Group Synaptic Plasticity, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
authors.forename: Tobias M
authors.initials: TM
authors.lastname: Rasse
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000378:metabolism; D004330:Drosophila; D005260:Female; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D020043:Genes, Essential; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism*; D010641:Phenotype; D013569:Synapses / Q000378:metabolism*
chemical_list: D018840:HSP70 Heat-Shock Proteins; C080352:mortalin