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

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.

Metabolic Markers and Association of Biological Sex in Lupus Nephritis

“…At the lower concentrations of LN or HC sera, the female-derived cells had a higher intracellular Ca 2+ flux indicating that the female-derived hRMCs have an increased sensitivity to serum stimulation. GSLs modulate cellular functions such as proliferation, apoptosis, migration, and signaling, including Ca 2+ signaling [6], and defects in GSL metabolism are associated with a variety of human diseases. GSLs expressed on the cell surface form clusters and are widely believed to play roles in the formation and stabilization of lipid domains ("lipid rafts") required to propagate extracellular signals.…”

“…Lactosylceramides (Lac-Cers) are generated from GlcCers. These GSLs are involved in a wide array of functions in most cell types, including proliferation, apoptosis, and signal transduction [2][3][4][5][6]. We previously demonstrated in a small cohort of subjects that LacCers were significantly elevated in the urine of lupus patients with nephritis compared to lupus patients without nephritis or healthy subjects [7].…”

An open chat with… Sandro Sonnino

“…Tatsuro Mutoh and colleagues then describe how disruptions in glycolipid and sphingolipid metabolism are observed in cases of encephalomyeloradiculoneuropathy (EMRN), which affects the brain, spinal cord, and peripheral nerves, and the involvement of such molecules in the immune system [ 3 ]. Concluding the section on neurodegenerative diseases, Alessandra d'Azzo and colleagues describe how ectopic accumulation of aberrantly processed/degraded glycosphingolipids can affect the topology of membrane contact sites, resulting in neurodegeneration [ 4 ]. Glycosphingolipids also play roles in other diseases, including cystic fibrosis and potentially some cases of male infertility; Massimo Aureli et al .…”