Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2023 Sep;13(9):1587-1600.
doi: 10.1002/2211-5463.13605. Epub 2023 Apr 17.

Glycosphingolipids within membrane contact sites influence their function as signaling hubs in neurodegenerative diseases

Jason Andrew Weesner  1 , Ida Annunziata  1   2 , Diantha van de Vlekkert  1 , Alessandra d'Azzo  1   3
Affiliations
Review

Glycosphingolipids within membrane contact sites influence their function as signaling hubs in neurodegenerative diseases

Jason Andrew Weesner et al. FEBS Open Bio. 2023 Sep.

Abstract

Intracellular organelles carry out many of their functions by engaging in extensive interorganellar communication through specialized membrane contact sites (MCSs) formed where two organelles tether to each other or to the plasma membrane (PM) without fusing. In recent years, these ubiquitous membrane structures have emerged as central signaling hubs that control a multitude of cellular pathways, ranging from lipid metabolism/transport to the exchange of metabolites and ions (i.e., Ca2+ ), and general organellar biogenesis. The functional crosstalk between juxtaposed membranes at MCSs relies on a defined composite of proteins and lipids that populate these microdomains in a dynamic fashion. This is particularly important in the nervous system, where alterations in the composition of MCSs have been shown to affect their functions and have been implicated in the pathogenesis of neurodegenerative diseases. In this review, we focus on the MCSs that are formed by the tethering of the endoplasmic reticulum (ER) to the mitochondria, the ER to the endo-lysosomes and the mitochondria to the lysosomes. We highlight how glycosphingolipids that are aberrantly processed/degraded and accumulate ectopically in intracellular membranes and the PM change the topology of MCSs, disrupting signaling pathways that lead to neuronal demise and neurodegeneration. In particular, we focus on neurodegenerative lysosomal storage diseases linked to altered glycosphingolipid catabolism.

Keywords: ER; endo-lysosome; glycosphingolipids; lysosomal storage diseases; membrane contact sites; mitochondria.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1
Membrane contact sites in LSDs: Physiological tethering complexes in (A) mitochondria‐lysosome MCSs, (B) mitochondria‐associated ER membranes and (C) ER‐lysosome MCSs that are dysregulated in LSDs. GlcCer can be found luminal or cytosolic within the ER membranes while all higher order GSLs are only found luminal in the organelles. GDP, guanosine diphosphate; GTP, guanosine‐5′‐triphophate; RAB7, Ras‐related protein 7; FIS1, mitochondrial fission 1 protein; TBC1D15, Tre2/Bub2/Cdc16 (TBC1)‐domain family member 15; VDAC‐1, voltage‐dependent anion channel protein 1; GRP75, glucose‐regulated protein 75; Ca2+, calcium; IP3, inositol 1,4,5‐triphosphate; IP3R1, inositol 1,4,5‐triphosphate receptor 1; NPC1, Niemann‐Pick disease, type C1; NPC2, Niemann‐Pick disease, type C2; mTORC1, mammalian target of rapamycin complex 1; Slc38A9, solute carrier family 38 member 9; V‐ATPase, vacuolar‐type ATPase; ORP1L, oxysterol‐binding protein‐related protein 1; VAP, VAMP (vesicle‐associated membrane protein)‐associated protein; SNX2, sorting nexin‐2; OSBP, oxysterol‐binding protein; GramD1B, GRAM domain containing 1B; Rag A/B, ras‐related GTP binding A/B; Rag C/D, ras‐related GTP binding C/D; Ragulator, pentameric complex (p18, p14, MP1, c7orf59, HBXIP); Kicstor, complex (KPTN, ITFG2, C12orf66, SZT2).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Casares D, Escribá PV and Rosselló CA (2019) Membrane lipid composition: effect on membrane and organelle structure, function and compartmentalization and therapeutic avenues. Int J Mol Sci 20, 2167. - PMC - PubMed
    1. O'Brien JS (1967) Cell membranes—composition: structure: function. J Theor Biol 15, 307–324. - PubMed
    1. Lamparter L and Galic M (2020) Cellular membranes, a versatile adaptive composite material. Front Cell Dev Biol 8, 684. - PMC - PubMed
    1. Bogdanov M, Dowhan W and Vitrac H (2014) Lipids and topological rules governing membrane protein assembly. Biochim Biophys Acta 1843, 1475–1488. - PMC - PubMed
    1. Muller MP, Jiang T, Sun C, Lihan M, Pant S, Mahinthichaichan P, Trifan A and Tajkhorshid E (2019) Characterization of lipid–protein interactions and lipid‐mediated modulation of membrane protein function through molecular simulation. Chem Rev 119, 6086–6161. - PMC - PubMed

Publication types

MeSH terms

Substances