title: Parkin functionally interacts with PGC-1α to preserve mitochondria and protect dopaminergic neurons.
abstract: To understand the cause of Parkinson's disease (PD), it is important to determine the functional interactions between factors linked to the disease. Parkin is associated with autosomal recessive early-onset PD, and controls the transcription of PGC-1α, a master regulator of mitochondrial biogenesis. These two factors functionally interact to regulate the turnover and quality of mitochondria, by increasing both mitophagic activity and mitochondria biogenesis. In cortical neurons, co-expressing PGC-1α and Parkin increases the number of mitochondria, enhances maximal respiration, and accelerates the recovery of the mitochondrial membrane potential following mitochondrial uncoupling. PGC-1α enhances Mfn2 transcription, but also leads to increased degradation of the Mfn2 protein, a key ubiquitylation target of Parkin on mitochondria. In vivo, Parkin has significant protective effects on the survival and function of nigral dopaminergic neurons in which the chronic expression of PGC-1α is induced. Ultrastructural analysis shows that these two factors together control the density of mitochondria and their interaction with the endoplasmic reticulum. These results highlight the combined effects of Parkin and PGC-1α in the maintenance of mitochondrial homeostasis in dopaminergic neurons. These two factors synergistically control the quality and function of mitochondria, which is important for the survival of neurons in Parkinson's disease.
authors.affiliation: Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
authors.forename: Lu
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bernard-Marissal
authors.affiliation: Laboratory of Integrative and Systems Physiology, EPFL, 1015 Lausanne, Switzerland.
authors.forename: Norman
authors.initials: N
authors.lastname: Moullan
authors.affiliation: Laboratory of Integrative and Systems Physiology, EPFL, 1015 Lausanne, Switzerland.
authors.forename: Davide
authors.initials: D
authors.lastname: D'Amico
authors.affiliation: Laboratory of Integrative and Systems Physiology, EPFL, 1015 Lausanne, Switzerland.
authors.forename: Johan
authors.initials: J
authors.lastname: Auwerx
authors.affiliation: Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.|Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI, 49503, USA.
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Moore
authors.affiliation: Centre of Interdisciplinary Electron Microscopy, EPFL, 1015 Lausanne, Switzerland.
authors.forename: Graham
authors.initials: G
authors.lastname: Knott
authors.affiliation: Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Aebischer
authors.affiliation: Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
authors.forename: Bernard L
authors.initials: BL
authors.lastname: Schneider
mesh_terms: D059290:Dopaminergic Neurons / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000235:genetics*; D005786:Gene Expression Regulation; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000235:genetics; D008928:Mitochondria / Q000235:genetics* / Q000473:pathology / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000235:genetics*; D001678:Organelle Biogenesis; D018384:Oxidative Stress / Q000235:genetics; D020734:Parkinsonian Disorders / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000235:genetics* / Q000378:metabolism; D059748:Proteolysis; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism
chemical_list: D024101:Mitochondrial Proteins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human