title: Mitochondrial defect and PGC-1α dysfunction in parkin-associated familial Parkinson's disease.
abstract: Mutations in the parkin gene are expected to play an essential role in autosomal recessive Parkinson's disease. Recent studies have established an impact of parkin mutations on mitochondrial function and autophagy. In primary skin fibroblasts from two patients affected by an early onset Parkinson's disease, we identified a hitherto unreported compound heterozygous mutation del exon2-3/del exon3 in the parkin gene, leading to the complete loss of the full-length protein. In both patients, but not in their heterozygous parental control, we observed severe ultrastructural abnormalities, mainly in mitochondria. This was associated with impaired energy metabolism, deregulated reactive oxygen species (ROS) production, resulting in lipid oxidation, and peroxisomal alteration. In view of the involvement of parkin in the mitochondrial quality control system, we have investigated upstream events in the organelles' biogenesis. The expression of the peroxisome proliferator-activated receptor gamma-coactivator 1-alpha (PGC-1α), a strong stimulator of mitochondrial biogenesis, was remarkably upregulated in both patients. However, the function of PGC-1α was blocked, as revealed by the lack of its downstream target gene induction. In conclusion, our data confirm the role of parkin in mitochondrial homeostasis and suggest a potential involvement of the PGC-1α pathway in the pathogenesis of Parkinson's disease. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease.
authors.affiliation: Department of Medical Biochemistry, Biology & Physics, University of Bari 'A. Moro', 70124 Bari, Italy.
authors.forename: Consiglia
authors.initials: C
authors.lastname: Pacelli
authors.forename: Domenico
authors.initials: D
authors.lastname: De Rasmo
authors.forename: Anna
authors.initials: A
authors.lastname: Signorile
authors.forename: Ignazio
authors.initials: I
authors.lastname: Grattagliano
authors.forename: Giuseppe
authors.initials: G
authors.lastname: di Tullio
authors.forename: Andria
authors.initials: A
authors.lastname: D'Orazio
authors.forename: Beatrice
authors.initials: B
authors.lastname: Nico
authors.forename: Giacomo Pietro
authors.initials: GP
authors.lastname: Comi
authors.forename: Dario
authors.initials: D
authors.lastname: Ronchi
authors.forename: Ermanno
authors.initials: E
authors.lastname: Ferranini
authors.forename: Domenico
authors.initials: D
authors.lastname: Pirolo
authors.forename: Peter
authors.initials: P
authors.lastname: Seibel
authors.forename: Susanna
authors.initials: S
authors.lastname: Schubert
authors.forename: Antonio
authors.initials: A
authors.lastname: Gaballo
authors.forename: Gaetano
authors.initials: G
authors.lastname: Villani
authors.forename: Tiziana
authors.initials: T
authors.lastname: Cocco
mesh_terms: D000328:Adult; D001483:Base Sequence; D017931:DNA Primers; D004734:Energy Metabolism; D005260:Female; D005347:Fibroblasts / Q000648:ultrastructure; D006360:Heat-Shock Proteins / Q000502:physiology*; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000502:physiology*; D009154:Mutation; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000235:genetics / Q000503:physiopathology*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*
chemical_list: D017931:DNA Primers; D006360:Heat-Shock Proteins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein