Membrane lipid raft homeostasis is directly linked to neurodegeneration

Abstract

Age-associated neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD) and Alzheimer’s disease (AD) are an unmet health need, with significant economic and societal implications, and an ever-increasing prevalence. Membrane lipid rafts (MLRs) are specialised plasma membrane microdomains that provide a platform for intracellular trafficking and signal transduction, particularly within neurons. Dysregulation of MLRs leads to disruption of neurotrophic signalling and excessive apoptosis which mirrors the final common pathway for neuronal death in ALS, PD and AD. Sphingomyelinase (SMase) and phospholipase (PL) enzymes process components of MLRs and therefore play central roles in MLR homeostasis and in neurotrophic signalling. We review the literature linking SMase and PL enzymes to ALS, AD and PD with particular attention to attractive therapeutic targets, where functional manipulation has been successful in preclinical studies. We propose that dysfunction of these enzymes is upstream in the pathogenesis of neurodegenerative diseases and to support this we provide new evidence that ALS risk genes are enriched with genes involved in ceramide metabolism (P=0.019, OR = 2.54, Fisher exact test). Ceramide is a product of SMase action upon sphingomyelin within MLRs, and it also has a role as a second messenger in intracellular signalling pathways important for neuronal survival. Genetic risk is necessarily upstream in a late age of onset disease such as ALS. We propose that manipulation of MLR structure and function should be a focus of future translational research seeking to ameliorate neurodegenerative disorders.

GLT8D1 mutations cause amyotrophic lateral sclerosis via disruption of neurotrophin signalling within membrane lipid rafts

“…In neurons, pro-survival signalling cascades occur predominantly through neurotrophin receptors associated with MLRs (Chiricozzi et al, 2020; Egawa et al, 2017; Moll et al, 2021; Zonta & Minichiello, 2013). These cascades are mediated through tropomyosin receptor kinases (Trk) and p75 neurotrophin receptors (p75 NTR ) (Moll et al, 2021). The localisation of neurotrophin receptors to MLRs is regulated by gangliosides, and multiple lines of evidence demonstrate that the ganglioside GM1 is essential for the activation of Trk receptors (Bachis et al, 2002; Duchemin et al, 2002; Farooqui et al, 1997; Mutoh et al, 1995; Pitto et al, 1998; Rabin et al, 2002).…”

“…In neurons, pro-survival signalling cascades occur predominantly through neurotrophin receptors associated with MLRs (Chiricozzi et al, 2020; Egawa et al, 2017; Moll et al, 2021; Zonta & Minichiello, 2013). These cascades are mediated through tropomyosin receptor kinases (Trk) and p75 neurotrophin receptors (p75 NTR ) (Moll et al, 2021).…”

“…Loss of ganglioside homeostasis appears to destabilise MLRs causing disrupted neurotrophin signalling. Impaired neurotrophin signalling through MLRs is a well-described feature of ALS pathophysiology (Head et al, 2011; Moll et al, 2021), and targeted re-stabilisation of MLRs via up-regulation of CAV1 has clear therapeutic potential (Egawa et al, 2017; Sawada et al, 2019; Wang et al, 2021). We have previously identified ALS-associated genetic variation within enhancer elements linked to the expression of CAV1.…”

“…Loss of ganglioside homeostasis appears to destabilise MLRs causing disrupted neurotrophin signalling. Impaired neurotrophin signalling through MLRs is a welldescribed feature of ALS pathophysiology (Head et al, 2011;Moll et al, 2021), and targeted (which was not certified by peer review) is the author/funder. All rights reserved.…”

“…Mature gangliosides are transported to the cell plasma membrane by vesiculation where they provide structure and stability to membrane lipid rafts (MLRs), specialised plasma membrane microdomains that regulate a wide range of cellular physiology including signal transduction, spatial organisation of the plasma membrane, and endocytosis (Grassi et al, 2020; Koyama-Honda et al, 2020; van IJzendoorn et al, 2020). In neurons, MLRs serve as platforms for pro-survival and pro-growth signalling cascades initiated by neurotrophic factors (e.g., BDNF/TrkB activation) (Moll et al, 2021; Pike, 2005; Sawada et al, 2019). Disrupted MLRs are associated with impaired neurotrophin signalling and consequent neurodegeneration (Sawada et al, 2019).…”