Lipid Involvement in Neurodegenerative Diseases of the Motor System: Insights from Lysosomal Storage Diseases

Abstract

Lysosomal storage diseases (LSDs) are a heterogeneous group of rare inherited metabolic diseases that are frequently triggered by the accumulation of lipids inside organelles of the endosomal-autophagic-lysosomal system (EALS). There is now a growing realization that disrupted lysosomal homeostasis (i.e., lysosomal cacostasis) also contributes to more common neurodegenerative disorders such as Parkinson disease (PD). Lipid deposition within the EALS may also participate in the pathogenesis of some additional neurodegenerative diseases of the motor system. Here, I will highlight the lipid abnormalities and clinical manifestations that are common to LSDs and several diseases of the motor system, including amyotrophic lateral sclerosis (ALS), atypical forms of spinal muscular atrophy, Charcot–Marie–Tooth disease (CMT), hereditary spastic paraplegia (HSP), multiple system atrophy (MSA), PD and spinocerebellar ataxia (SCA). Elucidating the underlying basis of intracellular lipid mislocalization as well as its consequences in each of these disorders will likely provide innovative targets for therapeutic research.

Ambroxol Hydrochloride Improves Motor Functions and Extends Survival in a Mouse Model of Familial Amyotrophic Lateral Sclerosis

“…Dysregulation of GlcCer and other glycosphingolipids (e.g., GM1a) was previously reported by us and others in ALS patients and in animal models (Dodge et al, 2015; Henriques et al, 2015; Dodge, 2017; Henriques et al, 2017; Henriques et al, 2018).…”

“…Beyond their role in energy metabolism, lipids and particularly sphingolipids are modulators of cellular signaling pathways and participate in the maintenance and repair of the various components of the motor axis such as neurons and muscles. Our transcriptomic studies on muscle biopsies in ALS patients showed a significant increase in the expression of the UGCG gene (UDP-glucose ceramide glucosyltransferase), encoding the sphingolipid metabolism enzyme that synthesizes glucosylceramide (GlcCer) (Henriques et al, 2015; Dodge, 2017; Henriques et al, 2017). It has been shown in ALS that GlcCer and ceramide levels are deregulated (Cutler et al, 2002; Dodge et al, 2015; Henriques et al, 2015; Henriques et al, 2018).…”

Sphingolipid Metabolism Is Dysregulated at Transcriptomic and Metabolic Levels in the Spinal Cord of an Animal Model of Amyotrophic Lateral Sclerosis

“…Elevated diacylglycerols have been reported in the frontal cortex of patients diagnosed with Alzheimer's disease (Wood et al, 2016 ) and levels of sphingolipids, phospholipids, and neutral lipids were reported as significantly dysregulated in the central nervous system (CNS) of patients diagnosed with Parkinson's disease (Cheng et al, 2011 ). Genetic mutations causing disrupted lipid metabolism have been linked to neurological and neuromuscular phenotypes in human diseases, like hereditary spastic paraplegia (Dodge, 2017 ).…”

Exploring Sphingolipid Implications in Neurodegeneration

“…Lipids perform the regulatory role by acting as secondary messengers in the inflammation processes during ALS development which are accompanied by the activation of microglia, loss of neuromuscular junctions, and subsequent degeneration of motor neurons. At the same time, the level of neurotoxic molecules synthesized with an active involvement of lipid messengers increases (93).…”