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.
Highlights
Membrane lipid rafts (MLRs) are specialised plasma membrane microdomains that are integral to the regulation of intracellular trafficking and signal transduction
their dysregulation is strongly linked with neurodegenerative disease
• MLR homeostasis is regulated by sphingomyelinase
Summary
Membrane lipid rafts (MLRs) are specialised plasma membrane microdomains that are integral to the regulation of intracellular trafficking and signal transduction. Phospholipase dysregulation disrupts MLRs and impairs neurotrophic signalling Phospholipases (PLs) catalyse the hydrolysis and cleavage of phospholipids [75] and play a central role in plasma membrane structure and homeostasis which includes MLRs. Phospholipids form the membrane permeability barrier, but they regulate membrane protein function and serve as second messengers in signal transduction pathways [76]. Alterations in activity, associated mechanisms, associated neurodegenerative disorder(s), potential as therapeutic target, and references are shown; AD, Alzheimer’s disease; ALS, amyotrophic lateral sclerosis; PD, Parkinson’s disease. Given their prominent role in apoptosis and neurotrophic signalling pathways, SMase and PL enzymes have been explored as potential therapeutic targets for ALS, PD and AD. An antisense oligonucleotide against cPLA2α administered to SOD1-G93A mice ameliorates disease-associated elevation in levels of cPL2Aα protein, delays symptom onset and prolongs survival while preventing motor neuron loss [104]
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