Lipids constitute approximately half of the dry weight of the brain, their composition and quantity can vary throughout life and generic defects in their synthesis or metabolism can lead to impaired brain development and neurodegenerative disorders, both in children and adults. However, we do not know everything about lipids and it is not surprising that these molecules have always represented an attractive issue for biochemists, geneticists and clinicians.
Brain is the organ with the highest concentration of lipids, second only to adipose tissue. Mammalian cells contain about 1000-2000 different species, classified into eight main categories (fatty acyls, glycerolipids, glycerophospholipids, sphingolipids, sterol lipids, prenol lipids, saccharolipids, and polyketides), which account for many several functions, like maintaining protein structure or providing energy reservoir.
A special issue of the journal Biochimica et Biophysica Acta, entitled “Brain lipid”, unveils the role of lipids in health and disease, with a special attention to their relationship with brain function. The genetic origin of monogenic disorders caused by impaired sphingolipid metabolism (SL), has been widely explored in the same issue by Thierry Levade and colleagues, from the Cancer Research Center in Toulouse. The authors also presented results obtained with animal models that try to mirror the specific genetic defects, although in some cases they cannot recapitulate the neurological phenotype observed in humans.
SLs are quite abundant in human brain, where they are considered not only essential membrane components, but also important signaling molecules that are required to regulate specific biochemical events. Tus. their concentration in the central nervous system has to be highly controlled. Indeed, accumulation of SLs, due to defects in the activity of enzyme responsible for their degradation, can cause severe disorders, as in the case of Gaucher, and Niemann-Pick A and B diseases.
Ceramide (Cer) is the simplest of SLs and because of its simplicity it can be combined with other molecules, modified in many different manners and even converted into as many products required for the correct metabolism. Mutations in the genes responsible for Cer synthesis have been associated to myoclonic epilepsy and progressive dementia, even though the mechanisms are largely unknown. Genetic alteration in the gene that codes for acid, lysosomal ceramidase, an enzyme that cleaves fatty acids from ceramide, is known to cause accumulation of Cer in tissues and body fluids, and to underlie Farber disease. On the other hand, mutations in the gene encoding acid sphingomyelinase, the enzyme that induces the hydrolysis of sphingomyelin (SM) to ceramide, are responsible for accumulation of SM in visceral tissues, lymph nodes and brain and for the onset of Niemann–Pick disease type A, a neurodegenerative disorder that can lead to death before 3 years of age. Since SMs are abundantly expressed in the membrane, it seems that alteration in membrane composition may have an effect on neuronal polarization and synaptic plasticity.
Galactosphingolipids are the primary constituents of myelin, the substance that covers the axon of the neurons and whose principal function is to increase the speed of signals transmitted between neurons. Defects in metabolism of galactosphingolipids cause severe neurological disorders including metachromatic leukodystrophy with its several clinical forms and Krabbe disease, where the infant form, the most severe, can cause developmental delay and death at 2 years of age.
Mutations in genes involved in the metabolism of gangliosides, firstly identified in brain ganglion cells, may cause Morquio disease and GM1-gangliosidosis, a disorder that leads to premature death in the most severe cases, and to many other progressive symptoms like hypotonia, locomotor disturbances, seizures, muscleweakness, lethargy, and strabismus. The mechanisms are still uncertain, but increased neuronal death has been observed in the brain of affected patients.
Over 300 pathogenic mutations in the gene encoding for β-glucosylceramidases, which usually lead to the accumulation of glucosylceramides in brain, cerebellum, and cerebrospinal fluid, can cause Gaucher disease, which can manifest in three different forms. However, although increased neuronal death has been observed, the pathway that links glucosylceramides and neurological disturbance in still unknown.
The understanding of the mechanisms that regulate lipid synthesis, accumulation and degradation may open new possibilities to the identification of lipid-targeting therapeutic approaches for neurological disorders.
A deeper study of the involvement of lipids as signaling molecules will also increase our knowledge about neuron activity and synaptic connections.
Sabourdy F. et al. Monogenic neurological disorders of sphingolipid metabolism. Biochim
Biophys Acta. 2015 Aug;1851(8):1040-51.
Dawson G.et al. Measuring brain lipids. Biochim Biophys Acta. 2015