Reducing GBA2 Activity Ameliorates Neuropathology in Niemann-Pick Type C Mice

The enzyme glucocerebrosidase (GBA) hydrolyses glucosylceramide (GlcCer) in lysosomes. Markedly reduced GBA activity is associated with severe manifestations of Gaucher disease including neurological involvement. Mutations in the GBA gene have recently also been identified as major genetic risk fact...

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Vydáno v:	PloS one Ročník 10; číslo 8; s. e0135889
Hlavní autoři:	Marques, André R. A., Aten, Jan, Ottenhoff, Roelof, van Roomen, Cindy P. A. A., Herrera Moro, Daniela, Claessen, Nike, Vinueza Veloz, María Fernanda, Zhou, Kuikui, Lin, Zhanmin, Mirzaian, Mina, Boot, Rolf G., De Zeeuw, Chris I., Overkleeft, Herman S., Yildiz, Yildiz, Aerts, Johannes M. F. G.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States Public Library of Science 14.08.2015 Public Library of Science (PLoS)
Témata:	Abnormalities Animals Basal ganglia beta-Glucosidase - genetics beta-Glucosidase - metabolism Biochemistry Biosynthesis Brain Brain diseases Central nervous system diseases Cholesterol Endoplasmic reticulum Enzymes Gaucher's disease Genetic disorders Glucosylceramidase Glucosylceramides - genetics Glucosylceramides - metabolism Intracellular Signaling Peptides and Proteins Life span Lysosomes Metabolic disorders Metabolism Mice Mice, Knockout Motor ability Mouse devices Movement disorders Mutation Neuropathology Neurosciences Niemann-Pick disease Niemann-Pick Disease, Type C - enzymology Niemann-Pick Disease, Type C - genetics Niemann-Pick Disease, Type C - pathology Npc1 protein Pathology Physiological aspects Proteins - genetics Proteins - metabolism Purkinje cells Purkinje Cells - enzymology Purkinje Cells - pathology Risk factors Substrates Therapeutic applications Yang, Cindy Netherlands
ISSN:	1932-6203, 1932-6203
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Shrnutí:	The enzyme glucocerebrosidase (GBA) hydrolyses glucosylceramide (GlcCer) in lysosomes. Markedly reduced GBA activity is associated with severe manifestations of Gaucher disease including neurological involvement. Mutations in the GBA gene have recently also been identified as major genetic risk factor for Parkinsonism. Disturbed metabolism of GlcCer may therefore play a role in neuropathology. Besides lysosomal GBA, cells also contain a non-lysosomal glucosylceramidase (GBA2). Given that the two β-glucosidases share substrates, we speculated that over-activity of GBA2 during severe GBA impairment might influence neuropathology. This hypothesis was studied in Niemann-Pick type C (Npc1-/-) mice showing secondary deficiency in GBA in various tissues. Here we report that GBA2 activity is indeed increased in the brain of Npc1-/- mice. We found that GBA2 is particularly abundant in Purkinje cells (PCs), one of the most affected neuronal populations in NPC disease. Inhibiting GBA2 in Npc1-/- mice with a brain-permeable low nanomolar inhibitor significantly improved motor coordination and extended lifespan in the absence of correction in cholesterol and ganglioside abnormalities. This trend was recapitulated, although not to full extent, by introducing a genetic loss of GBA2 in Npc1-/- mice. Our findings point to GBA2 activity as therapeutic target in NPC.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Competing Interests: The authors have declared that no competing interests exist. Conceived and designed the experiments: ARAM JA RO DHM MFVV KZ RGB CIDZ JMFGA. Performed the experiments: ARAM JA RO CPAAvR DHM NC MFVV KZ ZL MM. Analyzed the data: ARAM JA DHM MFVV KZ RGB CIDZ JMFGA. Contributed reagents/materials/analysis tools: HSO YY. Wrote the paper: ARAM JA RGB CIDZ JMFGA.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0135889