共 57 条
Progranulin associates with hexosaminidase A and ameliorates GM2 ganglioside accumulation and lysosomal storage in Tay-Sachs disease
被引:40
作者:

Chen, Yuehong
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NYU, Med Ctr, Dept Orthopaed Surg, 301 East 17th St, New York, NY 10003 USA
Sichuan Univ, West China Hosp, Dept Rheumatol & Immunol, Chengdu 610041, Sichuan, Peoples R China NYU, Med Ctr, Dept Orthopaed Surg, 301 East 17th St, New York, NY 10003 USA

Jian, Jinlong
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NYU, Med Ctr, Dept Orthopaed Surg, 301 East 17th St, New York, NY 10003 USA NYU, Med Ctr, Dept Orthopaed Surg, 301 East 17th St, New York, NY 10003 USA

Hettinghouse, Aubryanna
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NYU, Med Ctr, Dept Orthopaed Surg, 301 East 17th St, New York, NY 10003 USA NYU, Med Ctr, Dept Orthopaed Surg, 301 East 17th St, New York, NY 10003 USA

Zhao, Xueheng
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Cincinnati Childrens Hosp Med Ctr, Div Human Genet, Cincinnati, OH 45229 USA NYU, Med Ctr, Dept Orthopaed Surg, 301 East 17th St, New York, NY 10003 USA

Setchell, Kenneth D. R.
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Cincinnati Childrens Hosp Med Ctr, Div Human Genet, Cincinnati, OH 45229 USA NYU, Med Ctr, Dept Orthopaed Surg, 301 East 17th St, New York, NY 10003 USA

Sun, Ying
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机构:
Cincinnati Childrens Hosp Med Ctr, Div Human Genet, Cincinnati, OH 45229 USA NYU, Med Ctr, Dept Orthopaed Surg, 301 East 17th St, New York, NY 10003 USA

Liu, Chuan-ju
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机构:
NYU, Med Ctr, Dept Orthopaed Surg, 301 East 17th St, New York, NY 10003 USA
NYU, Sch Med, Dept Cell Biol, New York, NY 10016 USA NYU, Med Ctr, Dept Orthopaed Surg, 301 East 17th St, New York, NY 10003 USA
机构:
[1] NYU, Med Ctr, Dept Orthopaed Surg, 301 East 17th St, New York, NY 10003 USA
[2] Sichuan Univ, West China Hosp, Dept Rheumatol & Immunol, Chengdu 610041, Sichuan, Peoples R China
[3] Cincinnati Childrens Hosp Med Ctr, Div Human Genet, Cincinnati, OH 45229 USA
[4] NYU, Sch Med, Dept Cell Biol, New York, NY 10016 USA
来源:
JOURNAL OF MOLECULAR MEDICINE-JMM
|
2018年
/
96卷
/
12期
关键词:
Tay-Sachs disease;
Lysosome storage disease;
Hexosaminidase A;
Progranulin;
Pcgin;
GROWTH-FACTOR;
MEMBRANE-LIPIDS;
TNF-ALPHA;
CHAPERONE;
ARTHRITIS;
PROTECTS;
BINDING;
IL-10;
DEATH;
HSP70;
D O I:
10.1007/s00109-018-1703-0
中图分类号:
Q3 [遗传学];
学科分类号:
071007 ;
090102 ;
摘要:
Tay-Sachs disease (TSD) is a lethal lysosomal storage disease (LSD) caused by mutations in the HexA gene, which can lead to deficiency of -hexosaminidase A (HexA) activity and consequent accumulation of its substrate, GM2 ganglioside. Recent reports that progranulin (PGRN) functions as a chaperone of lysosomal enzymes and its deficiency is associated with LSDs, including Gaucher disease and neuronal ceroid lipofuscinosis, prompted us to screen the effects of recombinant PGRN on lysosomal storage in fibroblasts from 11 patients affected by various LSDs, which led to the isolation of TSD in which PGRN demonstrated the best effects in reducing lysosomal storage. Subsequent in vivo studies revealed significant GM2 accumulation and the existence of typical TSD cells containing zebra bodies in both aged and ovalbumin-challenged adult PGRN-deficient mice. In addition, HexA, but not HexB, was aggregated in PGRN-deficient cells. Furthermore, recombinant PGRN significantly reduced GM2 accumulation and lysosomal storage in these animal models. Mechanistic studies indicated that PGRN bound to HexA through granulins G and E domain and increased the enzymatic activity and lysosomal delivery of HexA. More importantly, Pcgin, an engineered PGRN derivative bearing the granulin E domain, also effectively bound to HexA and reduced the GM2 accumulation. Collectively, these studies not only provide new insights into the pathogenesis of TSD but may also have implications for developing PGRN-based therapy for this life-threatening disorder.Key messagesGM2 accumulation and the existence of typical TSD cells containing zebra bodies are detected in both aged and ovalbumin-challenged adult PGRN deficient mice.Recombinant PGRN significantly reduces GM2 accumulation and lysosomal storage both in vivo and in vitro, which works through increasing the expression and lysosomal delivery of HexA.Pcgin, an engineered PGRN derivative bearing the granulin E domain, also effectively binds to to HexA and reduces GM2 accumulation.
引用
收藏
页码:1359 / 1373
页数:15
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NYU, Sch Med, Dept Orthopaed Surg, New York, NY 10003 USA
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Wang, Da-Wei
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Tang, Wei
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Texas A&M Univ Syst, Hlth Sci Ctr, Baylor Coll Dent, Dept Biomed Sci, Dallas, TX USA NYU, Sch Med, Dept Orthopaed Surg, New York, NY 10003 USA

Liu, Chuan-Ju
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机构: Univ Wurzburg, Inst Clin Neurobiol, DE-97080 Wurzburg, Germany

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机构: Univ Wurzburg, Inst Clin Neurobiol, DE-97080 Wurzburg, Germany