Journal Article

DZNE-2023-00443

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Glucocerebrosidase is imported into mitochondria and preserves complex I integrity and energy metabolism.

Baden, P. (First author)DZNE* ; Perez, M. J. (First author)DZNE* ; Raji, H.DZNE* ; Bertoli, F.DZNE* ; Kalb, S.DZNE* ; Illescas, M. ; Spanos, F.DZNE* ; Giuliano, C.DZNE* ; Calogero, A. M. ; Oldrati, M.DZNE* ; Hebestreit, H.DZNE* ; Cappelletti, G. ; Brockmann, K.DZNE* ; Gasser, T.DZNE* ; Schapira, A. H. V. ; Ugalde, C. ; Deleidi, M. (Last author)DZNE*

2023
Nature Publishing Group UK [London]

This record in other databases:    

Please use a persistent id in citations: doi:10.1038/s41467-023-37454-4

Abstract: Mutations in GBA1, the gene encoding the lysosomal enzyme β-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.

Keyword(s): Humans (MeSH) ; Glucosylceramidase: genetics (MeSH) ; Glucosylceramidase: metabolism (MeSH) ; Proteomics (MeSH) ; Parkinson Disease: metabolism (MeSH) ; Mitochondria: genetics (MeSH) ; Mitochondria: metabolism (MeSH) ; Energy Metabolism: genetics (MeSH) ; Mutation (MeSH) ; Lysosomes: metabolism (MeSH) ; alpha-Synuclein: metabolism (MeSH) ; Mitochondrial Proteins: metabolism (MeSH) ; ATP-Dependent Proteases: metabolism (MeSH) ; Glucosylceramidase ; alpha-Synuclein ; LONP1 protein, human ; Mitochondrial Proteins ; ATP-Dependent Proteases

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Contributing Institute(s):

1. Mitochondria and Inflammation in Neurodegeneration (AG Deleidi)
2. Parkinson Genetics (AG Gasser 1)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)
2. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2023

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Database coverage:
; ; ; ; Article Processing Charges ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Agriculture, Biology and Environmental Sciences ; Current Contents - Life Sciences ; Current Contents - Physical, Chemical and Earth Sciences ; DOAJ Seal ; Essential Science Indicators ; Fees ; IF >= 15 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection ; Zoological Record

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Linked articles:

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Dataset Stein, F. ; Deleidi, M.DZNE*
Dataset: GBA1 interactome for understanding pathological mechanisms
PRoteomics IDEntifications Database (2023)2023   Fulltext BibTeX | EndNote: XML, Text | RIS

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