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000257563 1001_ $$0P:(DE-2719)2811884$$aBaden, Pascale$$b0$$eFirst author$$udzne
000257563 245__ $$aGlucocerebrosidase is imported into mitochondria and preserves complex I integrity and energy metabolism.
000257563 260__ $$a[London]$$bNature Publishing Group UK$$c2023
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000257563 520__ $$aMutations 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.
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000257563 650_7 $$0EC 3.2.1.45$$2NLM Chemicals$$aGlucosylceramidase
000257563 650_7 $$2NLM Chemicals$$aalpha-Synuclein
000257563 650_7 $$0EC 3.4.21.-$$2NLM Chemicals$$aLONP1 protein, human
000257563 650_7 $$2NLM Chemicals$$aMitochondrial Proteins
000257563 650_7 $$0EC 3.4.21.-$$2NLM Chemicals$$aATP-Dependent Proteases
000257563 650_2 $$2MeSH$$aHumans
000257563 650_2 $$2MeSH$$aGlucosylceramidase: genetics
000257563 650_2 $$2MeSH$$aGlucosylceramidase: metabolism
000257563 650_2 $$2MeSH$$aProteomics
000257563 650_2 $$2MeSH$$aParkinson Disease: metabolism
000257563 650_2 $$2MeSH$$aMitochondria: genetics
000257563 650_2 $$2MeSH$$aMitochondria: metabolism
000257563 650_2 $$2MeSH$$aEnergy Metabolism: genetics
000257563 650_2 $$2MeSH$$aMutation
000257563 650_2 $$2MeSH$$aLysosomes: metabolism
000257563 650_2 $$2MeSH$$aalpha-Synuclein: metabolism
000257563 650_2 $$2MeSH$$aMitochondrial Proteins: metabolism
000257563 650_2 $$2MeSH$$aATP-Dependent Proteases: metabolism
000257563 7001_ $$0P:(DE-2719)9001465$$aPerez, Maria Jose$$b1$$eFirst author$$udzne
000257563 7001_ $$0P:(DE-2719)9001799$$aRaji, Hariam$$b2$$udzne
000257563 7001_ $$0P:(DE-2719)9001762$$aBertoli, Federico$$b3$$udzne
000257563 7001_ $$0P:(DE-2719)9000602$$aKalb, Stefanie$$b4$$udzne
000257563 7001_ $$00000-0003-0198-1106$$aIllescas, María$$b5
000257563 7001_ $$0P:(DE-2719)9001584$$aSpanos, Fokion$$b6$$udzne
000257563 7001_ $$0P:(DE-2719)2814785$$aGiuliano, Claudio$$b7$$udzne
000257563 7001_ $$00000-0003-2262-4992$$aCalogero, Alessandra Maria$$b8
000257563 7001_ $$0P:(DE-2719)9000688$$aOldrati, Marvin$$b9$$udzne
000257563 7001_ $$0P:(DE-2719)9001914$$aHebestreit, Hannah$$b10$$udzne
000257563 7001_ $$00000-0003-0903-5392$$aCappelletti, Graziella$$b11
000257563 7001_ $$0P:(DE-2719)2811916$$aBrockmann, Kathrin$$b12$$udzne
000257563 7001_ $$0P:(DE-2719)2320009$$aGasser, Thomas$$b13
000257563 7001_ $$00000-0002-3018-3966$$aSchapira, Anthony H V$$b14
000257563 7001_ $$00000-0002-9742-1877$$aUgalde, Cristina$$b15
000257563 7001_ $$0P:(DE-2719)2810385$$aDeleidi, Michela$$b16$$eLast author
000257563 773__ $$0PERI:(DE-600)2553671-0$$a10.1038/s41467-023-37454-4$$gVol. 14, no. 1, p. 1930$$n1$$p1930$$tNature Communications$$v14$$x2041-1723$$y2023
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