Cholesterol homeostatic responses provide biomarkers for monitoring treatment for the neurodegenerative disease Niemann-Pick C1 (NPC1)

被引：33

作者：

Tortelli, Brett ^{[1
,2
]}

Fujiwara, Hideji ^{[1
,2
]}

Bagel, Jessica H. ^{[3
]}

Zhang, Jessie ^{[1
,2
]}

Sidhu, Rohini ^{[1
,2
]}

Jiang, Xuntian ^{[1
,2
]}

Yanjanin, Nicole M. ^{[4
]}

Shankar, Roopa Kanakatti ^{[4
]}

Carillo-Carasco, Nuria ^{[5
]}

Heiss, John ^{[5
]}

Ottinger, Elizabeth ^{[6
]}

Porter, Forbes D. ^{[4
]}

Schaffer, Jean E. ^{[1
,2
]}

Vite, Charles H. ^{[3
]}

Ory, Daniel S. ^{[1
,2
]}

机构：

[1] Washington Univ, Sch Med, Diabet Cardiovasc Dis Ctr, St Louis, MO 63110 USA

[2] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA

[3] Univ Penn, Sch Vet Med, Dept Clin Studies, Philadelphia, PA 19104 USA

[4] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Dept Hlth & Human Serv, Program Dev Endocrinol & Genet, Bethesda, MD USA

[5] NINDS, Dept Hlth & Human Serv, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA

[6] NCATS, Therapeut Rare & Neglected Dis TRND Program, Bethesda, MD USA

来源：

HUMAN MOLECULAR GENETICS | 2014年 / 23卷 / 22期

基金：

美国国家卫生研究院;

关键词：

CYCLODEXTRIN OVERCOMES; MOUSE MODEL; PLASMA; MIGLUSTAT; TRANSPORT; BRAIN; 2-HYDROXYPROPYL-BETA-CYCLODEXTRIN; IDENTIFICATION; ACCUMULATION; DEGENERATION;

D O I：

10.1093/hmg/ddu331

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Niemann-Pick C1 (NPC1) disease is a rare, neurodegenerative lysosomal cholesterol storage disorder, typified by progressive cognitive and motor function impairment. Affected individuals usually succumb to the disease in adolescence. 2-Hydroxypropyl-beta-cyclodextrin (HP-beta-CD) has emerged as a promising intervention that reduces lipid storage and prolongs survival in NPC1 disease animal models. A barrier to the development of HP-beta-CD and other treatments for NPC disease has been the lack of validated biochemical measures to evaluate efficacy. Here we explored whether cholesterol homeostatic responses resulting from HP-beta-CD-mediated redistribution of sequestered lysosomal cholesterol could provide biomarkers to monitor treatment. Upon direct CNS delivery of HP-beta-CD, we found increases in plasma 24(S)-HC in two independent NPC1 disease animal models, findings that were confirmed in humanNPC1 subjects receiving HP-beta-CD. Since circulating 24(S)-HC is almost exclusively CNS-derived, the increase in plasma 24(S)-HC provides a peripheral, non-invasive measure of the CNS effect of HP-beta-CD. Our findings suggest that plasma 24(S)-HC, along with the other cholesterol-derived markers examined in this study, can serve as biomarkers that will accelerate development of therapeutics for NPC1 disease.

引用

页码：6022 / 6033

页数：12

共 56 条

[41] A novel cholesterol stain reveals early neuronal cholesterol accumulation in the Niemann-Pick type C1 mouse brain [J].