Category: Choreas (Non-Huntington's Disease)
Objective: To study the overall lipid composition and distribution in red blood cells (RBCs) and neurons derived from VPS13A disease patients, a neurodegenerative disorder associated with deficient bulk lipid transfer between organelles.
Background: VPS13A disease (chorea-acanthocytosis) is an ultra-rare disease caused by pathogenic variants in the VPS13A gene. The disorder is characterized by neurodegeneration mainly in the striatum causing a Huntington’s disease-like phenotype and by the presence of misshaped RBCs referred to as acanthocytes. As shown only recently, VPS13A is a bridge-like protein located to membrane contact sites connecting the endoplasmic reticulum (ER) with mitochondria and lipid droplets mediating bulk lipid transfer. The exact function and regulation of this protein, however, remain elusive.
Method: RBCs were collected from 5 VPS13A disease patients and 12 healthy control subjects for mass-spectrometry analysis (lipidomics analysis). Live-cell imaging was performed with patient (iPSC)-derived neurons using a super-resolution microscope. Cells were stained with Mito Tracker (mitochondrial marker), BFP-KDEL (ER marker) and 18:1 NBD-PS (fluorescent phosphatidylserine species) or 18:1 NBD-PE (fluorescent phosphatidylethanolamine species) to observe phospholipid distribution within neurons.
Results: In RBCs we found no significant differences on the lipid class level, but changes were noted in certain species, particularly in the phosphatidylethanolamine class. In this class, some species with longer fatty acid chains tended to be increased, while species with shorter fatty acid chains tended to be decreased. In iPSC-derived neurons, accumulation of NBD-PE in mitochondria and ER and of NBD-PS in mitochondria was observed.
Conclusion: Our results indicate alterations of the composition and distribution of particular lipid species in cellular models of VPS13A disease. Further studies are needed to unravel the role of lipid distribution in the pathophysiology of VPS13A disease and, more generally, of a new group of related disorders with disturbed bulk lipid transfer between organelles.
To cite this abstract in AMA style:K. Peikert, A. Spranger, E. Fischer, H. Glaß, B. Falkenburger, G. Miltenberger-Miltenyi, D. Tyteca, C. Klose, D. Grossmann, A. Hermann. Disorder of bulk lipid transfer? Lipid composition and distribution in cellular models of VPS13A disease [abstract]. Mov Disord. 2023; 38 (suppl 1). https://www.mdsabstracts.org/abstract/disorder-of-bulk-lipid-transfer-lipid-composition-and-distribution-in-cellular-models-of-vps13a-disease/. Accessed September 27, 2023.
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MDS Abstracts - https://www.mdsabstracts.org/abstract/disorder-of-bulk-lipid-transfer-lipid-composition-and-distribution-in-cellular-models-of-vps13a-disease/