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 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.
Department of Medical Biochemistry, Academic Medical Center, 1105 AZ, Amsterdam, The Netherlands.
André R A
AR
Marques
Department of Pathology, Academic Medical Center, 1105 AZ, Amsterdam, The Netherlands.
Jan
J
Aten
Department of Medical Biochemistry, Academic Medical Center, 1105 AZ, Amsterdam, The Netherlands.
Roelof
R
Ottenhoff
Department of Medical Biochemistry, Academic Medical Center, 1105 AZ, Amsterdam, The Netherlands.
Cindy P A A
CP
van Roomen
Department of Medical Biochemistry, Academic Medical Center, 1105 AZ, Amsterdam, The Netherlands.
Daniela
D
Herrera Moro
Department of Pathology, Academic Medical Center, 1105 AZ, Amsterdam, The Netherlands.
Nike
N
Claessen
Department of Neuroscience, Erasmus MC, 3000 CA, Rotterdam, The Netherlands.
María Fernanda
MF
Vinueza Veloz
Department of Neuroscience, Erasmus MC, 3000 CA, Rotterdam, The Netherlands.
Kuikui
K
Zhou
Department of Neuroscience, Erasmus MC, 3000 CA, Rotterdam, The Netherlands.
Zhanmin
Z
Lin
Department of Medical Biochemistry, Academic Medical Center, 1105 AZ, Amsterdam, The Netherlands.
Mina
M
Mirzaian
Department of Medical Biochemistry, Academic Medical Center, 1105 AZ, Amsterdam, The Netherlands.
Rolf G
RG
Boot
Department of Neuroscience, Erasmus MC, 3000 CA, Rotterdam, The Netherlands; Netherlands Institute for Neuroscience, Royal Dutch Academy of Arts & Sciences, 1105 BA, Amsterdam, The Netherlands.
Chris I
CI
De Zeeuw
Leiden Institute of Chemistry, Leiden University, 2300 RA, Leiden, The Netherlands.
Herman S
HS
Overkleeft
Department of Internal Medicine, Hospital of Bregenz, 6900, Bregenz, Austria.
Yildiz
Y
Yildiz
Department of Medical Biochemistry, Academic Medical Center, 1105 AZ, Amsterdam, The Netherlands; Leiden Institute of Chemistry, Leiden University, 2300 RA, Leiden, The Netherlands.
Johannes M F G
JM
Aerts
D000818:Animals; D005963:Glucosylceramides / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D011689:Purkinje Cells / Q000201:enzymology / Q000473:pathology; D001617:beta-Glucosidase / Q000235:genetics / Q000378:metabolism*
D005963:Glucosylceramides; D047908:Intracellular Signaling Peptides and Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; D001617:beta-Glucosidase; C517538:beta-glucosidase 2, mouse