Glucocerebrosidase deficiency in dopaminergic neurons induces microglial activation without neurodegeneration.
Human Molecular Genetics. 2017-05-17; 26(14): 2603-2615
DOI: 10.1093/hmg/ddx120
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Soria FN(1)(2), Engeln M(1)(2), Martinez-Vicente M(3), Glangetas C(1)(2), López-González MJ(4)(5), Dovero S(1)(2), Dehay B(1)(2), Normand E(4)(5), Vila M(3), Favereaux A(4)(5), Georges F(1)(2), Lo Bianco C(6), Bezard E(1)(2), Fernagut PO(1)(2).
Author information:
(1)UMR 5293, Institut des Maladies Neurodégénératives, Université de Bordeaux, 33076 Bordeaux, France.
(2)CNRS, UMR 5293, Institut des Maladies Neurodégénératives, 33076 Bordeaux, France.
(3)Vall d’Hebron Research Institute, CIBERNED and Catalan Institution for Research and Advanced Studies (ICREA), Autonomous University of Barcelona (UAB), Barcelona, Spain.
(4)UMR 5297, Interdisciplinary Institute of Neurosciences, Université de Bordeaux, 33076 Bordeaux, France.
(5)CNRS, UMR 5297, Interdisciplinary Institute of Neurosciences, 33076 Bordeaux, France.
(6)Neurodegenerative Disease Department, Merck Serono Institute, Geneva, Switzerland.
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.