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  Enriched expression of neutral sphingomyelinase 2 in the striatum is essential for regulation of lipid raft content and motor coordination

Tan, L.-H.-R., Tan, A.-J.-R., Ng, Y.-Y., Chua, J. J. E., Chew, W.-S., Muralidharan, S., et al. (2018). Enriched expression of neutral sphingomyelinase 2 in the striatum is essential for regulation of lipid raft content and motor coordination. Molecular Neurobiology, 55(7), 5741-5756. doi:10.1007/s12035-017-0784-z.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0001-F473-A Version Permalink: http://hdl.handle.net/21.11116/0000-0001-F478-5
Genre: Journal Article

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 Creators:
Tan, L. H.-R., Author
Tan, A. J.-R., Author
Ng, Y.-Y., Author
Chua, J. J. E.1, Author              
Chew, W.-S., Author
Muralidharan, S., Author
Torta, F., Author
Dutta, B., Author
Sze, S. K., Author
Herr, D. R., Author
Ong, W.-Y., Author
Affiliations:
1Research Group of Protein Trafficking in Synaptic Development and Function, MPI for Biophysical Chemistry, Max Planck Society, ou_1933287              

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Free keywords: nSMase2; Motor function; Startle reflex; Lipid rafts; GW4869; Antisense knockdown; Membrane lipids; Microdomains; Lipidomics; Proteomics; Sphingolipids
 Abstract: Sphingomyelinases are a family of enzymes that hydrolyze sphingomyelin to generate phosphocholine and ceramide. The brain distribution and function of neutral sphingomyelinase 2 (nSMase2) were elucidated in this study. nSMase2 mRNA expression was greatest in the striatum, followed by the prefrontal cortex, hippocampus, cerebellum, thalamus, brainstem, and olfactory bulb. The striatum had the highest level of nSMase2 protein expression, followed by the prefrontal cortex, thalamus, hippocampus, brainstem, and cerebellum. Dense immunolabeling was observed in the striatum, including the caudate-putamen, while moderately dense staining was found in the olfactory bulb and cerebral neocortex. Electron microscopy of the caudate-putamen showed nSMase2 immunoreaction product was present in small diameter dendrites or dendritic spines, that formed asymmetrical synapses with unlabeled axon terminals containing small round vesicles; and characteristics of glutamatergic axons. Lipidomic analysis of the striatum showed increase in long chain sphingomyelins, SM36:1 and SM38:1 after inhibition of nSMase activity. Quantitative proteomic analysis of striatal lipid raft fraction showed many proteins were downregulated by more than 2-fold after inhibition or antisense knockdown of nSMase; consistent with the notion that nSMase2 activity is important for aggregation or clustering of proteins in lipid rafts. Inhibition or antisense knockdown of nSMase2 in the caudate-putamen resulted in motor deficits in the rotarod and narrow beam tests; as well as decreased acoustic startle and improved prepulse inhibition of the startle reflex. Together, results indicate an important function of nSMase2 in the striatum.

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Language(s): eng - English
 Dates: 2017-10-172018-07
 Publication Status: Published in print
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 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1007/s12035-017-0784-z
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Title: Molecular Neurobiology
Source Genre: Journal
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Pages: - Volume / Issue: 55 (7) Sequence Number: - Start / End Page: 5741 - 5756 Identifier: -