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Glucocerebrosidase is imported into mitochondria and preserves complex I integrity and energy metabolism.
Baden, Pascale; Perez, Maria Jose; Raji, Hariam; Bertoli, Federico; Kalb, Stefanie; Illescas, María; Spanos, Fokion; Giuliano, Claudio; Calogero, Alessandra Maria; Oldrati, Marvin; Hebestreit, Hannah; Cappelletti, Graziella; Brockmann, Kathrin; Gasser, Thomas; Schapira, Anthony H V; Ugalde, Cristina; Deleidi, Michela.
Afiliação
  • Baden P; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
  • Perez MJ; Department of Neurodegenerative Diseases, Center of Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
  • Raji H; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815, USA.
  • Bertoli F; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
  • Kalb S; Department of Neurodegenerative Diseases, Center of Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
  • Illescas M; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815, USA.
  • Spanos F; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
  • Giuliano C; Department of Neurodegenerative Diseases, Center of Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
  • Calogero AM; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815, USA.
  • Oldrati M; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
  • Hebestreit H; Department of Neurodegenerative Diseases, Center of Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
  • Cappelletti G; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815, USA.
  • Brockmann K; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
  • Gasser T; Department of Neurodegenerative Diseases, Center of Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
  • Schapira AHV; Instituto de Investigación Hospital 12 de Octubre (i + 12), Madrid, 28041, Spain.
  • Ugalde C; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
  • Deleidi M; Department of Neurodegenerative Diseases, Center of Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
Nat Commun ; 14(1): 1930, 2023 04 06.
Article em En | MEDLINE | ID: mdl-37024507
ABSTRACT
Mutations in GBA1, the gene encoding the lysosomal enzyme ß-glucocerebrosidase (GCase), which cause Gaucher's disease, are the most frequent genetic risk factor for Parkinson's disease (PD). Here, we employ global proteomic and single-cell genomic approaches in stable cell lines as well as induced pluripotent stem cell (iPSC)-derived neurons and midbrain organoids to dissect the mechanisms underlying GCase-related neurodegeneration. We demonstrate that GCase can be imported from the cytosol into the mitochondria via recognition of internal mitochondrial targeting sequence-like signals. In mitochondria, GCase promotes the maintenance of mitochondrial complex I (CI) integrity and function. Furthermore, GCase interacts with the mitochondrial quality control proteins HSP60 and LONP1. Disease-associated mutations impair CI stability and function and enhance the interaction with the mitochondrial quality control machinery. These findings reveal a mitochondrial role of GCase and suggest that defective CI activity and energy metabolism may drive the pathogenesis of GCase-linked neurodegeneration.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Doença de Parkinson / Glucosilceramidase Idioma: En Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Doença de Parkinson / Glucosilceramidase Idioma: En Ano de publicação: 2023 Tipo de documento: Article