TY - JOUR
T1 - Reducing GBA2 activity ameliorates neuropathology in niemann-pick type C mice
AU - Marques, André R.A.
AU - Aten, Jan
AU - Ottenhoff, Roelof
AU - Van Roomen, Cindy P.A.A.
AU - Moro, Daniela Herrera
AU - Claessen, Nike
AU - Veloz, María Fernanda Vinueza
AU - Zhou, Kuikui
AU - Lin, Zhanmin
AU - Mirzaian, Mina
AU - Boot, Rolf G.
AU - De Zeeuw, Chris I.
AU - Overkleeft, Herman S.
AU - Yildiz, Yildiz
AU - Aerts, Johannes M.F.G.
N1 - Publisher Copyright:
© 2015 Marques et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2015/8/14
Y1 - 2015/8/14
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/84942894832
U2 - 10.1371/journal.pone.0135889
DO - 10.1371/journal.pone.0135889
M3 - 文章
C2 - 26275242
AN - SCOPUS:84942894832
SN - 1932-6203
VL - 10
JO - PLoS ONE
JF - PLoS ONE
IS - 8
M1 - e0135889
ER -