Visualisation of cholesterol and ganglioside GM1 in zebrafish models of Niemann-Pick type C disease and Smith-Lemli-Opitz syndrome using light sheet microscopy

Cook, Sophie R, Bladen, Cerys, Smith, Johanna, Maguire, Emily, Copner, Jordan, Fenn, Gareth D, Wager, Kim ORCID: https://orcid.org/0000-0001-8107-9600, Waller-Evans, Helen ORCID: https://orcid.org/0000-0003-4133-6064 and Lloyd-Evans, Emyr ORCID: https://orcid.org/0000-0002-3626-1611 2020. Visualisation of cholesterol and ganglioside GM1 in zebrafish models of Niemann-Pick type C disease and Smith-Lemli-Opitz syndrome using light sheet microscopy. Histochemistry and Cell Biology 154 , pp. 565-578. 10.1007/s00418-020-01925-2

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Abstract

Lysosomal storage diseases are the most common cause of neurodegeneration in children. They are characterised at the cellular level by the accumulation of storage material within lysosomes. There are very limited therapeutic options, and the search for novel therapies has been hampered as few good small animal models are available. Here, we describe the use of light sheet microscopy to assess lipid storage in drug and morpholino induced zebrafish models of two diseases of cholesterol homeostasis with lysosomal dysfunction: First, Niemann–Pick type C disease (NPC), caused by mutations in the lysosomal transmembrane protein NPC1, characterised by intralysosomal accumulation of cholesterol and several other lipids. Second, Smith–Lemli–Opitz syndrome (SLOS), caused by mutations in 7-dehydrocholesterol reductase, which catalyses the last step of cholesterol biosynthesis and is characterised by intralysosomal accumulation of dietary cholesterol. This is the first description of a zebrafish SLOS model. We find that zebrafish accurately model lysosomal storage and disease-specific phenotypes in both diseases. Increased cholesterol and ganglioside GM1 were observed in sections taken from NPC model fish, and decreased cholesterol in SLOS model fish, but these are of limited value as resolution is poor, and accurate anatomical comparisons difficult. Using light sheet microscopy, we were able to observe lipid changes in much greater detail and identified an unexpected accumulation of ganglioside GM1 in SLOS model fish. Our data demonstrate, for the first time in zebrafish, the immense potential that light sheet microscopy has in aiding the resolution of studies involving lysosomal and lipid disorders.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Pharmacy Biosciences
Publisher:	Springer Verlag (Germany)
ISSN:	0948-6143
Funders:	MRC
Date of First Compliant Deposit:	28 September 2020
Date of Acceptance:	22 September 2020
Last Modified:	06 Mar 2024 02:07
URI:	https://orca.cardiff.ac.uk/id/eprint/135176

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