Glucocerebrosidase deficiency in dopaminergic neurons induces microglial activation without neurodegeneration
| Autor: | Alexandre Favereaux, Pierre-Olivier Fernagut, Federico N. Soria, Marta Martinez-Vicente, Erwan Bezard, François Georges, Christophe Lo Bianco, Miquel Vila, Christelle Glangetas, Sandra Dovero, Benjamin Dehay, María José López-González, Michel Engeln, Elisabeth Normand |
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| Přispěvatelé: | Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Vall d’Hebron Research Institute (VHIR), Interdisciplinary Institute for Neuroscience [Bordeaux] (IINS), Neurodegenerative Disease Department, Merck & Co. Inc, CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France., Interdisciplinary Institute for Neuroscience (IINS), Dehay, Benjamin |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
[SDV]Life Sciences [q-bio] Genetic Vectors Substantia nigra Biology 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Dopamine Mesencephalon Genetics medicine Animals Molecular Biology Genetics (clinical) Neuroinflammation Alpha-synuclein Mice Knockout Gaucher Disease Microglia Dopaminergic Neurons Neurodegeneration Dopaminergic Brain Parkinson Disease General Medicine medicine.disease Cell biology [SDV] Life Sciences [q-bio] Substantia Nigra 030104 developmental biology medicine.anatomical_structure chemistry nervous system Models Animal alpha-Synuclein Glucosylceramidase Glucocerebrosidase 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Human Molecular Genetics Human Molecular Genetics, Oxford University Press (OUP), 2017, 26 (14), pp.2603-2615. ⟨10.1093/hmg/ddx120⟩ Human Molecular Genetics, 2017, 26 (14), pp.2603-2615. ⟨10.1093/hmg/ddx120⟩ |
| ISSN: | 0964-6906 1460-2083 |
| DOI: | 10.1093/hmg/ddx120⟩ |
| Popis: | International audience; Mutations in the GBA1 gene encoding the lysosomal enzyme glucocerebrosidase (GBA1) are important risk factors for Parkinson's disease (PD). In vitro, altered GBA1 activity promotes alpha-synuclein accumulation whereas elevated levels of alpha-synuclein compromise GBA1 function, thus supporting a pathogenic mechanism in PD. However, the mechanisms by which GBA1 deficiency is linked to increased risk of PD remain elusive, partially because of lack of aged models of GBA1 deficiency. As knocking-out GBA1 in the entire brain induces massive neurodegeneration and early death, we generated a mouse model of GBA1 deficiency amenable to investigate the long-term consequences of compromised GBA1 function in dopaminergic neurons. DAT-Cre and GBA1-floxed mice were bred to obtain selective homozygous disruption of GBA1 in midbrain dopamine neurons (DAT-GBA1-KO). Mice were followed for motor function, neuronal survival, alpha-synuclein phosphorylation and glial activation. Susceptibility to nigral viral vector-mediated overexpression of mutated (A53T) alpha-synuclein was assessed. Despite loss of GBA1 and substrate accumulation, DAT-GBA1-KO mice displayed normal motor performances and preserved dopaminergic neurons despite robust microglial activation in the substantia nigra, without accumulation of endogenous alpha-synuclein with respect to wild-type mice. Lysosomal function was only marginally affected. Screening of micro-RNAs linked to the regulation of GBA1, alpha-synuclein or neuroinflammation did not reveal significant alterations. Viral-mediated overexpression of A53T-alpha-synuclein yielded similar neurodegeneration in DAT-GBA1-KO mice and wild-type mice. These results indicate that loss of GBA1 function in mouse dopaminergic neurons is not critical for alpha-synuclein accumulation or neurodegeneration and suggest the involvement of GBA1 deficiency in other cell types as a potential mechanism. |
| Databáze: | OpenAIRE |
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