Membrane lipid rafts and neurobiology: age‐related changes in membrane lipids and loss of neuronal function

Abstract

A better understanding of the cellular physiological role that plasma membrane lipids, fatty acids and sterols play in various cellular systems may yield more insight into how cellular and whole organ function is altered during the ageing process. Membrane lipid rafts (MLRs) within the plasma membrane of most cells serve as key organizers of intracellular signalling and tethering points of cytoskeletal components. MLRs are plasmalemmal microdomains enriched in sphingolipids, cholesterol and scaffolding proteins; they serve as a platform for signal transduction, cytoskeletal organization and vesicular trafficking. Within MLRs are the scaffolding and cholesterol binding proteins named caveolin (Cav). Cavs not only organize a multitude of receptors including neurotransmitter receptors (NMDA and AMPA receptors), signalling proteins that regulate the production of cAMP (G protein‐coupled receptors, adenylyl cyclases, phosphodiesterases (PDEs)), and receptor tyrosine kinases involved in growth (Trk), but also interact with components that modulate actin and tubulin cytoskeletal dynamics (e.g. RhoGTPases and actin binding proteins). MLRs are essential for the regulation of the physiology of organs such as the brain, and age‐related loss of cholesterol from the plasma membrane leads to loss of MLRs, decreased presynaptic vesicle fusion, and changes in neurotransmitter release, all of which contribute to different forms of neurodegeneration. Thus, MLRs provide an active membrane domain that tethers and reorganizes the cytoskeletal machinery necessary for membrane and cellular repair, and genetic interventions that restore MLRs to normal cellular levels may be exploited as potential therapeutic means to reverse the ageing and neurodegenerative processes.

Frequency‐dependent lipid raft uptake at rat diaphragm muscle axon terminals

“…Lipid rafts are structurally unique microdomains of plasma membranes, crucial for neural development and function, including synaptic transmission and neurotrophic signaling . These microdomains are enriched in sphingolipids, cholesterol‐binding proteins, and scaffolding proteins.…”

Methamphetamine reduces expression of caveolin-1 in the dorsal striatum: Implication for dysregulation of neuronal function

“…In the context of the above hypothesis, Cavs are cholesterol-binding and scaffolding proteins within MLRs in neurons, and function as organizers of plasmalemmal signaling molecules including G-protein coupled receptors (assist with receptor internalization and trafficking to the recycling endosomes) (Head et al, 2014, Egawa et al, 2015). Cavs are present in three isoforms (Williams and Lisanti, 2004).…”

Simvastatin treatment reduces the cholesterol content of membrane/lipid rafts, implicating the N -methyl-D-aspartate receptor in anxiety: a literature review

“…Its channel commonly has a high relative permeability to Ca 2+ , and it is blocked in a voltagedependent manner by magnesium ions such that at resting potential the response is substantially inhibited. Cholesterol depletion is reported to lead to an inhibition of Ca 2+ entry induced by NMDA, AMPA, or kainate, inferring that MLRs contribute to the regulation of ionotropic glutamate receptor function (Egawa et al, 2016;Frank et al, 2008). Numerous post-synaptic density proteins such as NMDA (NR1, NR2A and NR2B), AMPA (GluR1 and GluR2), and metabotropic glutamate receptors (mGluRs) are associated with synaptic MLRs, providing a trans-synaptic link between postsynaptic density proteins and pre-synaptic active zones (Egawa et al, 2016;Kumari, Castillo, Francesconi, 2013).…”

“…Cholesterol depletion is reported to lead to an inhibition of Ca 2+ entry induced by NMDA, AMPA, or kainate, inferring that MLRs contribute to the regulation of ionotropic glutamate receptor function (Egawa et al, 2016;Frank et al, 2008). Numerous post-synaptic density proteins such as NMDA (NR1, NR2A and NR2B), AMPA (GluR1 and GluR2), and metabotropic glutamate receptors (mGluRs) are associated with synaptic MLRs, providing a trans-synaptic link between postsynaptic density proteins and pre-synaptic active zones (Egawa et al, 2016;Kumari, Castillo, Francesconi, 2013). Accumulating evidence suggests that MLRs clustering is a novel mechanism mediating and amplifying transmembrane signaling in response to various stimuli in a variety of cell types, including lymphocytes, endothelial cells, and neurons (Dupree, Pomicter, 2010;Grassme et al, 2001;Zhang et al, 2006).…”