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. 2023 Dec 14:17:1321250.
doi: 10.3389/fnins.2023.1321250. eCollection 2023.

Pharmacological interventions for lipid transport disorders

Aaron M Neiman  1
Affiliations

Pharmacological interventions for lipid transport disorders

Aaron M Neiman. Front Neurosci. .

Abstract

The recent discovery that defects in inter-organelle lipid transport are at the heart of several neurological and neurodegenerative disorders raises the challenge of identifying therapeutic strategies to correct lipid transport defects. This perspective highlights two potential strategies suggested by the study of lipid transport in budding yeast. In the first approach, small molecules are proposed that enhance the lipid transfer activity of VPS13 proteins and thereby compensate for reduced transport. In the second approach, molecules that act as inter-organelle tethers could be used to create artificial contact sites and bypass the loss of endogenous contacts.

Keywords: Parkinson’s disease; VPS13 genes; lipid transport; membrane contact site (MCS); neuroacanthocytosis; proteolysis-targeting chimeric (PROTAC) molecule.

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Conflict of interest statement

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Proposed models for rescue of lipid transport in VPS13 mutant cells. (A) Wild-type transport at a VPS13-mediated contact site. VPS13 protein (blue oval) can transfer lipids between membranes through a hydrophobic channel in the protein. (B) Rescue by a transport enhancer. In the presence of a defective VPS13 (indicated by the ‘X’), transport is stopped. A transport enhancer (gray box) triggers a conformational change in the VPS13 protein restoring transport function. (C) Rescue by a bypass agent. In cells entirely lacking VPS13, new contact sites can be created by introducing a bifunctional cross linker that creates an artificial contact site between the two membranes. Other lipid transport proteins (LTPs) in the cell can then mediate lipid transport at these artificial contacts.
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