Direct and indirect role of lipids in Motor Neuron Disease
Acetyl-Lcarnitine and Neuroprotection

Author: maurizio grassano
Date: 19/01/2015


Lipids play a key role, even if not fully understood, in SNC metabolism and function. Lipid metabolism has therefore become subject of several studies for its implication in pathogenesis and treatment of the disease, especially in the family of motor neuron disease (MND), among which the most common is the Amyotrophic lateral Sclerosis (ALS).

Lipid and membrane fluidity in neuron damage

Cellular functions and survival depend, other than on the activity of protein and enzymes in the cytoplasm, on the composition in lipids of plasmatic membranes. Membrane phospholipids in the CNS are rich in PUFA and in particular of docosahexaenoic acid (DHA).
Enrichment of sphingolipids and cholesterol and the content in polyunsaturated fatty acids (PUFA), directly determines membrane fluidity, thus affecting the movement of membrane proteins in lipid rafts , specialized membrane microdomain of protein receptor and glycosphingolipidis (Lipid rafts as a membrane-organizing principle. 2010).

Image 1. Lipid Raft structure

The level of these lipids has been demonstrated to be altered in many diseaese, especially degenerative disease involving the central nervous system, including Alzheimer disease and ALS.

Indeed, pathological alteration of lipid levels can be found in ALS patients and SOD1 mice (SOD1 knock-out mice are the only available model of ALS and motoneuron disease): the loss of membrane fluidity is likely to be an important factor in the development and progression of the neuron damage, beacuse in SOD1 mice the alteration in lipid composition of the membrane precede the disease onset (Levels of membrane fluidity in the spinal cord and the brain in an animal model of amyotrophic lateral sclerosis, 2011) presumably because even little changes in the membrane fluidity could widely affect a range of cellular functions, including ligand-receptor signal transduction and membrane trafficking, with disastrous consequences on cell functions and survival.

Aberrant accumulation of ceramides is commonly seen as being toxic. It mediates neuron death by oxidative stress and apoptosis in animal models and patients of neurodegenerative diseases (The role of ceramides in selected brain pathologies: ischemia/hypoxia, Alzheimer disease, 2012, Increased ceramide in brains with Alzheimer's and other neurodegenerative diseases, 2012) . Ceramides are precursor molecules at the crossroads of the sphingolipid metabolism and they can be converted into sphingomyelin, ceramide-1-phosphate and gangliosides. Abnormal repartition of gangliosides was described in the CNS of ALS patients and presence of antibodies anti-gangliosides has been described in their serum: anti-ganglioside antibodies are associated to the Guillain-Barré Syndrome, a peripheral neuropathy that may follow a Campylobacter Jejuni infection. Anti-ganglioside antibodies, however, may also bind to the peripheral nerve (more specifically, to the Ranvier Node) and activate the complement cascade without causing an acute conduction block: it has been postulated that antibodies may then play an undefined role in the pathogenesis of chronic and neurodegenerative disease.
Gangliosides are important for axonal function and regeneration, and neuronal survival (Inhibition of ganglioside synthesis reduces the neuronal survival activity of astrocytes, 2011).

Energetic metabolism in the motor unit

In the motor unit, both the muscles and the motor neurons show alteration in lipid metabolism. However, it is still unclear if this abnormality represents one of the multiple causes of the disease or it should be considered as consequences of the damage.
Apparently, in ALS disease large motor neurons are more vulnerable to changes in lipid metabolism than slow motor neuron, potentially due to their higher energetic needs. The more intense metabolism could also be a source of oxidative stress. The altered lipid beta oxidation in the CNS of ALS patients could also results from abnormally enhanced levels of ketone bodies, wich neurons can use as energetic substrate in absence of glucose.

The loss of large motor neurons induces a metabolic shift in muscle fibers from glycolytic to oxidative: SOD1 muscles consumes more fatty acids, and an abnormal expression profile of genes involved in lipid metabolism could be observed (Decreased mRNA expression of PGC-1alpha and PGC-1alpha-regulated factors in the SOD1G93A alS mouse model and in human sporadic als, 2012 ). This predominance of oxidative metabolism involves a deficiency in oxidative mitochondrial chain function, but the mechanism are under investigation. However, the mitochodrial disfunction is likely the result from the interaction of different pathways.

Among the possible pathways involved, there are two that appear to assume a fundamental role in mitochondrial biogenesis and functions: peroxisome proliferator-activated receptor gamma coactivator (PGC-1 alpha) and Stearoyl-Coa desaturase 1 (SCD-1). The downregulation of PGC-1 alpha cause significant modification of lipid metabolism, and impacts the use of fatty acids. Moreover Sirtuin 3, a downstream target of PGC-1 alpha, protects neurons in vitro against SOD1 G85R (the main variant of SOD in familial ALS) aggregation and toxicity (Molecular chaperone Hsp110 rescues a vesicle transport defect produced by an alS-associated mutant SOD1 protein in squid axoplasm, 2013).

Image 2. PGC-1 pathway in lipid metabolism control and in mitocondrial biosynthesis

Stearoyl-Coa desaturase 1 (SCD-1), who is a key enzyme in the regulation of lipid metabolism, is thought to be central in the mithocondrial alteration resulting in cellular disfunctional metabolism and death. SCD-1 role is the introduction of a double bond in the carbon chain of saturated fatty acids, to generated mono-unsaturated fatty acids: mono-unsatured fatty acids tend to be stored in fat tissues rather then used as an energetic source. The function of SCD-1 is associated to regulation of energetic metabolism, and most particularly the management of lipid reserves. Downregulation of SCD-1 is then supposed to induce an increased expression of genes involved in the beta-oxidation of fatty acids, increasing energy expenditure and reducing fat storage. On the other hand, mono-unsaturated fatty acids, produced by SCD-1, favor cytotoxic SOD-1 aggregation (Unsaturated fatty acids induce cytotoxic aggregate formation of amyotrophic lateral sclerosis-linked superoxide dismutase 1 mutants, 2005), and the accumulation of toxic lipid species such as ceramide (Stearoyl-CoA desaturase-1 deficiency reduces ceramide synthesis by downregulating serine palmitoyltransferase and increasing beta-oxidation in skeletal muscle, 2005), suggesting that loss of SCD-1 activity could lower cytotoxicity in MND. The overall effect of altered expression of SCD-1 in vivo appear to be more complex then expected, and need further study. In addition from its role in energetic metabolism, SCD-1 is involved required in the synthesis of complex lipids (phospholipids above all): regulation of SCD-1 might affect different cellular functions, including membrane fluidity and signaling, through mechanism not entirely known.

Image 3. SCD-1 role in in cellular damage and degenerative disorders

Another key element in mitochondrial metabolism, with important implications in both pathogenesis and treatment of neurodegenerative disease, is carnitine.

Fatty acids as signaling molecules

In addition to their role in the membrane structure, PUFA also have intrinsic functions on cell signaling, not only regulating energetic metabolism. First, PUFA are known to bind to transcription factors, such as liver-X receptor (LXR) and retinoic-X receptor (RXR), to stimulate the expression of genes involved in energy homeostasis: dysregulation of their levels contribute to the altered metabolism observed in ALS. Besides, PUFA also induce (or protect from) neuroinflammation, a complex biochemical response that seems to play a key role in promoting and maintaining the neural damage.
PUFA can in fact be converted into active molecules: these derivates present either pro-inflammatory (for omega 6 fatty acids) or anti-inflammatory and neuroprotective effects (omega 3 fatty acids), depending on the site of the unsaturation. For instance, eicosapentaenoic and arachidonic acids can be oxidized to prostanglandins ( PGE2, for instance, is synthetized by cyclooxygenase-2 from the arachidonic acid, an omega 6 fatty acid, in order to induce inflammation after binding to its receptor) or leukotrienes, while the oxidation of docosahexaenoic acid produces the neuroprotectin D1, a signaling molecule that promotes beneficial effects on cell survival under stress (Endogenous signaling by omega-3 docosahexaenoic acid-derived mediators sustains homeostatic synaptic and circuitry integrity, 2011).
The omega 3 fatty acids can be converted into anti-inflammatory and neuroprotective molecules.

Image 4. How Neuroprotectin D1 protects cell from oxidative stress and neuroinflammation

Potential implication in therapy

The increasing knowledge in lipids role in neurodegenerative disease led to the development of several different drugs (even if only the acetylcarnitine has a clear indication in the treatment of peripheral nerve injury):

  • General mitochondrial activity, including mitochondrial proliferation, could represents an interesting therapeutic target for ALS (Sirtuins as therapeutic targets of alS, 2013 ,"Mitochondria and alS. Implications from novel genes and pathways, 2013":
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