title: PARK2 enhancement is able to compensate mitophagy alterations found in sporadic Alzheimer's disease.
abstract: Mitochondrial anomalies have been previously reported in patients' brain and peripheral tissue, suggesting their relevance in sporadic Alzheimer's disease (AD). The present work evaluates mitochondrial function and recycling in human fibroblasts and brain biopsies. Functional studies using patients' skin fibroblasts showed slower mitochondrial membrane potential recovery after a mitochondrial insult together with alterations in lysosomes and autophagy, accompanied by an increase of oxidized and ubiquitinated proteins. Impairment in mitophagy has been proven in these cells due to diminished PARK2 and insufficient vesicle induction, accumulating depolarized mitochondria and PINK1. Augmented Δ1 PINK1 fragment levels suggest an inhibitory effect over PARK2 translocation to the mitochondria, causing the accumulation of activated PINK1. Moreover, the overexpression of PARK2 diminished ubiquitinated proteins accumulation, improves its targeting to mitochondria and potentiates autophagic vesicle synthesis. This allows the reversion of mitophagy failure reflected in the recovery of membrane potential and the decrease of PINK1 and mitochondria accumulation. Sporadic AD fibroblasts exhibited alterations similar to what it could be found in patients' hippocampal samples at early stages of the disease, where there was an accumulation of PINK1 and Δ1 PINK1 together with abnormally increased mitochondrial content. Our findings indicate that mitophagy alterations can be considered a new hallmark of sporadic AD and validate the use of fibroblasts for modelling this pathology.
authors.affiliation: Centro de Biología Molecular 'Severo Ochoa' (UAM-CSIC), Nicolás Cabrera, 1. Cantoblanco, 28049 Madrid, Spain, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Valderrebollo, 5, 28031 Madrid, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Martín-Maestro
authors.affiliation: Centro de Biología Molecular 'Severo Ochoa' (UAM-CSIC), Nicolás Cabrera, 1. Cantoblanco, 28049 Madrid, Spain, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Valderrebollo, 5, 28031 Madrid, Spain, Centro Nacional de Biotecnología (CSIC), Darwin, 3, Cantoblanco, 28049 Madrid, Spain.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Gargini
authors.affiliation: University of Texas at San Antonio, One UTSA Circle, San Antonio, TX 78249-0667, USA and.
authors.forename: George
authors.initials: G
authors.lastname: Perry
authors.affiliation: Centro de Biología Molecular 'Severo Ochoa' (UAM-CSIC), Nicolás Cabrera, 1. Cantoblanco, 28049 Madrid, Spain, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Valderrebollo, 5, 28031 Madrid, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Avila
authors.affiliation: Centro de Biología Molecular 'Severo Ochoa' (UAM-CSIC), Nicolás Cabrera, 1. Cantoblanco, 28049 Madrid, Spain, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Valderrebollo, 5, 28031 Madrid, Spain, Departamento de Anatomía, Histología y Neurociencia, Facultad de Medicina, UAM, Arzobispo Morcillo, 4, 28029 Madrid, Spain v.garcia-escudero@csic.es v.garcia-escudero@uam.es.
authors.forename: Vega
authors.initials: V
authors.lastname: García-Escudero
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D001343:Autophagy / Q000502:physiology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008247:Lysosomes / Q000378:metabolism / Q000473:pathology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology*; D024101:Mitochondrial Proteins / Q000378:metabolism; D063306:Mitophagy / Q000502:physiology*; D061251:Primary Cell Culture; D011494:Protein Kinases / Q000378:metabolism; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000008:administration & dosage / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D000099202:PTEN-Induced Putative Kinase
chemical_list: D024101:Mitochondrial Proteins; D011494:Protein Kinases; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C111567:parkin protein