TY - JOUR
T1 - Critical role for glycosphingolipids in Niemann-Pick disease type C
AU - Zervas, Mark
AU - Somers, Kyra L.
AU - Thrall, Mary Anna
AU - Walkley, Steven U.
N1 - Funding Information:
We thank Peter Pentchev for kindly providing the NPC nih /NPC nih mice and Oxford GlycoSciences for supplying the N B-DNJ. This study was supported by the Ara Parseghian Medical Research Foundation (S.U.W.) and by grants from the National Institutes of Health (NS07098 [M.Z.], DK09627 [K.S.], and RR06886 [M.A.T.]).
PY - 2001/8/21
Y1 - 2001/8/21
N2 - Niemann-Pick type C (NPC) disease is a cholesterol lipidosis caused by mutations in NPC1 and NPC2 gene loci [1]. Most human cases are caused by defects in NPC1 [2], as are the spontaneously occurring NPC diseases in mice [3] and cats [4]. NPC1 protein possesses a sterol-sensing domain [1-3] and has been localized to vesicles that are believed to facilitate the recycling of unesterified cholesterol from late endosomes/lysosomes to the ER and Golgi [1, 5-7]. In addition to accumulating cholesterol, NPC1-deficient cells also accumulate gangliosides and other glycosphingolipids (GSLs), and neuropathological abnormalities in NPC disease closely resemble those seen in primary gangliosidoses [1, 8-12]. These findings led us to hypothesize that NPC1 may also function in GSL homeostasis [9]. To evaluate this possibility, we treated murine and feline NPC models with N-butyldeoxynojirimycin (NB-DNJ), an inhibitor of glucosylceramide synthase, a pivotal enzyme in the early GSL synthetic pathway [13, 14]. Treated animals showed delayed onset of neurological dysfunction, increased average life span (in mice), and reduced ganglioside accumulation and accompanying neuropathological changes. These results are consistent with our hypothesis and with GSLs being centrally involved in the pathogenesis of NPC disease, and they suggest that drugs inhibiting GSL synthesis could have a similar ameliorating effect on the human disorder.
AB - Niemann-Pick type C (NPC) disease is a cholesterol lipidosis caused by mutations in NPC1 and NPC2 gene loci [1]. Most human cases are caused by defects in NPC1 [2], as are the spontaneously occurring NPC diseases in mice [3] and cats [4]. NPC1 protein possesses a sterol-sensing domain [1-3] and has been localized to vesicles that are believed to facilitate the recycling of unesterified cholesterol from late endosomes/lysosomes to the ER and Golgi [1, 5-7]. In addition to accumulating cholesterol, NPC1-deficient cells also accumulate gangliosides and other glycosphingolipids (GSLs), and neuropathological abnormalities in NPC disease closely resemble those seen in primary gangliosidoses [1, 8-12]. These findings led us to hypothesize that NPC1 may also function in GSL homeostasis [9]. To evaluate this possibility, we treated murine and feline NPC models with N-butyldeoxynojirimycin (NB-DNJ), an inhibitor of glucosylceramide synthase, a pivotal enzyme in the early GSL synthetic pathway [13, 14]. Treated animals showed delayed onset of neurological dysfunction, increased average life span (in mice), and reduced ganglioside accumulation and accompanying neuropathological changes. These results are consistent with our hypothesis and with GSLs being centrally involved in the pathogenesis of NPC disease, and they suggest that drugs inhibiting GSL synthesis could have a similar ameliorating effect on the human disorder.
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U2 - 10.1016/S0960-9822(01)00396-7
DO - 10.1016/S0960-9822(01)00396-7
M3 - Article
C2 - 11525744
AN - SCOPUS:0035928841
SN - 0960-9822
VL - 11
SP - 1283
EP - 1287
JO - Current Biology
JF - Current Biology
IS - 16
ER -