期刊
MOLECULAR GENETICS AND METABOLISM
卷 119, 期 1-2, 页码 144-150出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.ymgme.2016.07.010
关键词
Acetylcholine; Alpha-galactosidase A; Fabty disease; Gene silencing; Neuropathy
资金
- NIDDK Intramural Research Program
- NINDS Intramural Research Program at the National Institutes of Health, Bethesda, MD
- Pfizer Inc., New York, NY [IIR WI171341]
Fabry disease is a glycosphingolipid storage disorder that is caused by a genetic deficiency of the enzyme alphagalactosidase A (AGA, EC 3.2.1.22). It is a multisystem disease that affects the vascular, cardiac, renal, and nervous systems. One of the hallmarks of this disorder is neuropathic pain and sympathetic and parasympathetic nervous dysfunction. The exact mechanism by which changes in AGA activity result in change in neuronal function is not clear, partly due to of a lack of relevant model systems. In this study, we report the development of an in vitro model system to study neuronal dysfunction in Fabry disease by using short-hairpin RNA to create a stable knock-down of AGA in the human cholinergic neuronal cell line, LA-N-2. We show that gene-silenced cells show specifically reduced AGA activity and store globotriaosylceramide. In gene-silenced cells, release of the neurotransmitter acetylcholine is significantly reduced, demonstrating that this model may be used to study specific neuronal functions such as neurotransmitter release in Fabry disease. Published by Elsevier Inc.
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