Niemann-Pick C-like endo-lysosomal dysfunction in DHDDS patient cells, a congenital disorder of glycosylation, can be treated with miglustat

Best, Hannah L., Cook, Sophie R., Waller-Evans, Helen ORCID: https://orcid.org/0000-0003-4133-6064 and Lloyd-Evans, Emyr ORCID: https://orcid.org/0000-0002-3626-1611 2025. Niemann-Pick C-like endo-lysosomal dysfunction in DHDDS patient cells, a congenital disorder of glycosylation, can be treated with miglustat. International Journal of Molecular Sciences 26 (4) , 1471. 10.3390/ijms26041471

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Abstract

DHDDS (dehydrodolichol diphosphate synthetase) and NgBR (Nogo-B Receptor) collectively form an enzymatic complex important for the synthesis of dolichol, a key component of protein N-glycosylation. Mutations in DHDDS and the gene encoding NgBR (NUS1) are associated with neurodevelopmental disorders that clinically present with epilepsy, motor impairments, and developmental delay. Previous work has demonstrated both DHDDS and NgBR can also interact with NPC2 (Niemann-Pick C (NPC) type 2), a protein which functions to traffic cholesterol out of the lysosome and, when mutated, can cause a lysosomal storage disorder (NPC disease) characterised by an accumulation of cholesterol and glycosphingolipids. Abnormal cholesterol accumulation has also been reported in cells from both individuals and animal models with mutations in NUS1, and suspected lipid storage has been shown in biopsies from individuals with mutations in DHDDS. Our findings provide further evidence for overlap between NPC2 and DHDDS disorders, showing that DHDDS patient fibroblasts have increased lysosomal volume, store cholesterol and ganglioside GM1, and have altered lysosomal Ca2+ homeostasis. Treatment of DHDDS cells, with the approved NPC small molecule therapy, miglustat, improves these disease-associated phenotypes, identifying a possible therapeutic option for DHDDS patients. These data suggest that treatment options currently approved for NPC disease may be translatable to DHDDS/NUS1 patients.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Publisher:	MDPI
ISSN:	1661-6596
Date of First Compliant Deposit:	3 February 2025
Date of Acceptance:	2 February 2025
Last Modified:	12 Feb 2025 12:32
URI:	https://orca.cardiff.ac.uk/id/eprint/175834

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