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.