ALS and Lipid Metabolism Quiz

Neuronal Lipid Metabolism

• Lipids are a fundamental class of organic molecules involved in diverse biological processes, categorized as fatty acids, triacylglycerols (TAGs), phospholipids, sterol lipids, and sphingolipids.
• Different lipid classes have specific roles in various neuronal cell populations, serving as energy sources, structural components, bioactive molecules, or a combination thereof.
• Abnormalities in lipid metabolism are implicated in amyotrophic lateral sclerosis (ALS) pathogenesis.
• These dysfunctions potentially contribute to neuromuscular junction denervation, mitochondrial dysfunction, excitotoxicity, impaired neuronal transport, cytoskeletal defects, inflammation, and reduced neurotransmitter release.
• Modulation of lipid metabolism pathways may provide novel therapeutic approaches for ALS.

Lipid Synthesis, Structure, and Transport

• Fatty acids are the fundamental building blocks of lipids, categorized by carbon chain length (short, medium, long, very long).
• Saturated fatty acids have only single bonds between carbons, while unsaturated fatty acids include double bonds.
• Microsomal fatty acid elongation adds carbons to the fatty acid chain, primarily in the endoplasmic reticulum (ER).
• Desaturation introduces double bonds, diversifying fatty acid structure and function.
• Fatty acid synthesis occurs in lipogenic tissues (e.g., adipose tissue, liver).
• Brain synthesizes many required saturated and monounsaturated fatty acids, but lacks the ability to synthesize polyunsaturated fatty acids (PUFAs).
• PUFAs are essential for brain function.
• Fatty acids are transported across the blood-brain barrier via passive diffusion and active transport mechanisms (e.g., fatty acid transport protein (FATP), fatty acid translocase/CD36, fatty acid-binding proteins (FABPs)).
• Caveolae are intracellular invaginations that also participate in fatty acid transport.

Triacylglycerol (TAGs)

• TAGs are composed of a glycerol backbone with three fatty acid chains.
• TAG synthesis mainly occurs in adipose tissue and liver, also in skeletal muscle, kidney, lung, heart, and brain via glycerol-3-phosphate and monoacylglycerol pathways.
• Lipolysis, the breakdown of TAGs, is essential for fatty acid release and distribution to various tissues.
• TAG transport relies on lipoproteins (HDL, LDL).

Phospholipids

• Phospholipids are categorized into glycerophospholipids (e.g., phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol, cardiolipin) and phosphosphingolipids.
• Synthesis occurs primarily in the endoplasmic reticulum (ER).
• Several transport mechanisms facilitate phospholipid movement (e.g., phosphatidylcholine-specific transfer protein (PC-TP), phosphatidylinositol transfer proteins, non-specific lipid transfer protein).

Sterol Lipids

• Cholesterol is a primary sterol lipid in mammals, critical for membrane structure and function.
• Cholesterol synthesis takes place through the mevalonate pathway in most nucleated cells.
• The brain utilizes both Kandutsch-Russell and Bloch pathways in cholesterol synthesis.
• Cholesterol transport occurs via both non-vesicular and vesicular mechanisms.

Sphingolipids

• Sphingolipids are characterized by a sphingosine backbone.
• Ceramide is a simple sphingolipid.
• Sphingomyelins, cerebrosides are more complex.
• Synthesis of sphingolipids starts in the endoplasmic reticulum.
• Different sphingolipids are trafficked to different membranes, according to their function.
• Glycosylceramide and sphingomyelin are transported to the Golgi and further modified.

Lipids as Energy Substrates

• Brain relies primarily on glucose for energy, though fatty acid oxidation contributes about 20%.
• Ketone bodies (e.g., acetoacetate, D-ß-hydroxybutyrate) are produced during periods of fasting.
• These provide an alternative energy source in situations of low glucose availability, although using them for sustained energy generation in the long run is detrimental to the brain.

Lipid Oxidation & Regulation

• β-oxidation breaks down fatty acids within mitochondria.
• It releases energy in the form of FADH2, NADH, and acetyl CoA, which enter the citric acid cycle for further ATP production.
• Peroxisomes also oxidize long-chain and branched fatty acids.
• The rate of fatty acid oxidation is tightly regulated by cellular energy status and other factors.

Neuronal Lipid Metabolism in ALS

• Lipid metabolism dysregulation is a feature of ALS, with significant alterations affecting energy metabolism, cell structure, and signaling.
• Increased oxidative stress, associated with lipid oxidation, leads to neuronal damage.
• Changes in lipid composition affect membrane fluidity and signaling.
• Dysfunction in sphingolipids and their transport is observed in ALS.