Lecture 6 - Neural Lipids in their Specialised Membranes

Why do nerve cells modify the lipid composition of their membranes?

To ease vesicle fusion, regulate ion fluxes, and create specialised microenvironments that contribute to cellular communication

How does the chemical diversity of membrane lipids affect cell function?

Controls protein traffic, facilitates recognition between cells, and produces hundreds of lipid mediators that carry information within and across cells

What proportion of the human brain (dry weight) is made up of lipids?

About half

What is the objective of neural lipidomics?

To understand how neural lipids work together and contribute to brain function

What is the structure of fatty acids?

What is the structure of glycerophospholipids?

What is the structure of sphingolipids?

What is the structure of sterol lipids?

What functional group is present at one end of a fatty acid?

A carboxyl group (–COOH)

What is found at the other end of a fatty acid?

A hydrophobic tail

Can fatty acids be saturated or unsaturated?

Yes, they can be either saturated or unsaturated

Are fatty acids ever free in membranes?

No, they are always attached to phospholipids or sphingolipids

What is one main role of fatty acids in the body?

Used in energy storage

What role do unsaturated fatty acids play in neurons?

Help maintain flexible membranes for synaptic function

What forms the backbone of glycerophospholipids?

Glycerol

How many fatty acid tails do glycerophospholipids have, and what is their property?

Two fatty acid tails, which are hydrophobic

What does the head group of glycerophospholipids contain, and what is its property?

A phosphate-containing head group, which is hydrophilic

Are glycerophospholipids amphiphilic or not?

Yes, they are amphiphilic

What structural role do glycerophospholipids play in cells?

They form the lipid bilayer of membranes

How do glycerophospholipids support membrane proteins?

They provide a platform for membrane proteins

Why are glycerophospholipids critical in neurons?

Essential for neuronal membranes and synaptic vesicles

What is the backbone of sphingolipids?

Sphingosine (not glycerol)

What molecule do sphingolipids often contain?

A fatty acid, forming a ceramide

What are the two main types of sphingolipids?

Sphingomyelin (a phospholipid) and glycosphingolipids (e.g., cerebrosides, gangliosides)

What structural role do sphingolipids play in cells?

They are components of cell membranes

What functional roles do sphingolipids have?

Involved in cell recognition and signal transduction

Why are sphingolipids important in the nervous system?

Defects can cause neurodegenerative and storage diseases

What is the core structure of sterol lipids?

A rigid four-ring structure

What is the most important sterol in the body?

Cholesterol

How do sterol lipids affect membranes?

They regulate membrane fluidity and stabilise lipid bilayers

Why are sterol lipids essential in the nervous system?

Required for myelin formation, synapse formation, and steroid hormone synthesis

What types of molecules are lipids?

Hydrophobic or amphipathic small molecules

How are lipids derived?

By condensation of hydrocarbon units in chains or rings

Are most lipids soluble in water?

No, most are not water-soluble

How abundant are poorly unsaturated fatty acids in normal cells versus the brain?

Rare in normal cells, but they make up most of the composition in the brain

What is the simplest phospholipid?

Phosphatidic acid

Which head group does phosphatidylethanolamine contain?

Ethanolamine

Which head group does phosphatidylcholine contain?

Choline

Which head group does phosphatidylserine contain?

Serine

Which head group does phosphatidylglycerol contain?

Glycerol

Which head group does phosphatidylinositol 4,5-bisphosphate contain?

myo-Inositol 4,5-bisphosphate

What is cardiolipin derived from?

Phosphatidyl-glycerol

Which phospholipid is zwitterionic rather than anionic?

Phosphatidylcholine

What types of fatty acid chains can phospholipids have?

Saturated, straight chains or cis-double bond kinked chains

What is the backbone of sphingolipids made of?

Sphingosine (no glycerol)

What is unique about the sphingosine backbone?

It always contains one trans double bond, making it very rigid

What is the simplest sphingolipid and what is its polar head?

Ceramide, with hydrogen as the polar head

Is ceramide toxic or non-toxic?

Toxic

Which sphingolipid has choline as the polar head and is the most common?

Sphingomyelin

What sugar do cerebrosides contain in the nervous system versus elsewhere?

Galactose in the nervous system, glucose elsewhere

How can cerebrosides be modified?

They can be sulfated to form sulfatides

What do globosides contain?

Two or more sugars

What do gangliosides contain?

Complex oligosaccharides (many sugars)

What is the functional role of attaching sugars to sphingolipids?

Allows for cell recognition

What is another name for Krabbe’s disease?

Globoid cell leukodystrophy

When do symptoms of Krabbe’s disease normally develop and what is the typical prognosis?

Symptoms develop before six months of age, with death usually by two years

What type of genetic inheritance does Krabbe’s disease have?

Autosomal-recessive

Which enzyme is deficient in Krabbe’s disease?

Galactosylceramidase (galactocerebroside β-galactosidase)

What type of disorder is Krabbe’s disease classified as?

A metabolic disorder

What happens to myelin and myelin-forming cells in Krabbe’s disease?

Rapid and nearly complete disappearance in CNS & PNS

What cellular changes are seen in Krabbe’s disease?

Reactive astrocytic gliosis and infiltration of multi-nucleated macrophages (globoid cells)

What is the normal function of galactosylceramidase?

Catabolises galactosylsphingosine (psychosine) into sphingosine and galactose

Why is Krabbe’s disease toxic to oligodendrocytes?

Accumulation of galactosylsphingosine (psychosine) is highly toxic to oligodendrocytes and other cells

What is the most abundant sterol in animals?

Cholesterol

What is the structure of cholesterol?

Small polar head, rigid sterol rings, and a flexible (floppy) tail

What is cholesterol a precursor for?

Bile acids, steroid hormones, and oxysterols

What structural role does cholesterol play in membranes?

Major component; controls membrane fluidity and packing, provides mechanical strength, and supports membrane organisation and stability

How water-soluble is cholesterol?

It is water-insoluble

What proportion of the body’s cholesterol is in the brain?

About 25%

What is the most abundant molecule in the myelin membrane and what role does it play?

Cholesterol; it drives myelination

What disease does the Npc1-/- mouse model represent?

Niemann-Pick Disease type C (lysosomal storage disorder)

What is defective in Niemann-Pick Disease type C?

A cholesterol transporter in lysosomes loses function

What happens to cholesterol in the Npc1-/- mouse?

Cholesterol is trapped in lysosomes and cannot be transferred to growing myelin sheaths

How do lipids function in energy storage in neural tissue?

As triglycerides and fatty acids

What structural role do lipids play in neural tissue?

Insulating myelin to reduce ion leakage and speed up electrical signals

What role do lipid microdomains (lipid rafts) play in neurons?

Control protein trafficking, neuronal polarisation, exocytosis, and rearranging dendritic spines for synaptic plasticity

How do lipids participate in signal transduction?

By directly binding to proteins (lipid anchors) and producing signalling molecules like endocannabinoids, eicosanoids, and docosanoids

What is the lipid and protein composition of the myelin sheath?

Lipid 80%, Protein 20%

How many lipids per protein are in the myelin sheath?

200 lipids per protein

What is the lipid and protein composition of the plasma membrane

Lipid 50%, Protein 50%

How many lipids per protein are in the plasma membrane?

50 lipids per protein

What is the lipid and protein composition of the inner mitochondrial membrane?

Lipid 25%, Protein 75%

How many lipids per protein are in the inner mitochondrial membrane?

40 lipids per protein

What are the most abundant lipids in myelin?

• Cholesterol

• Galactocerebroside

• Sulfatide

• Plasmalogens

Who first studied the structure of myelin around 1950?

Betty Geren and James Robertson

How is myelin structured around an axon?

As a spiral wrap of the oligodendrocyte (CNS) or Schwann cell (PNS) membrane

What does the glial cell do during myelin formation?

Extends a sheet of membrane around the axon

What happens to cytoplasm and extracellular matrix during myelin wrapping?

Most cytoplasm inside the cell and extracellular matrix outside are squeezed out

What holds the layers of myelin together?

Protein-lipid and protein-protein interactions

What is the role of Myelin Basic Protein (MBP)?

Major cytoplasmic adhesive protein; binds inner surfaces of myelin

What is the role of Proteolipid Protein (PLP)?

Stabilises extracellular membrane contacts

How do sulfatides and Gal-Cerebrosides contribute to myelin?

Interact with PLP to stabilise compact myelin

What is MAG (Myelin-Associated Glycoprotein) and where is it expressed?

Minor myelin protein expressed on the inner surface of myelin near axons, especially at paranodal junctions

How do gangliosides support the axon-myelin interface?

Interact with MAG on the axonal membrane to support the axon-myelin connection

How do plasmalogen levels change with age?

Increase up to 30–40 years, then decline with age

What neurological condition has been linked to loss of plasmalogens?

Onset of dementia in Alzheimer’s disease

How do plasmalogens affect myelin membranes?

They are more compact than regular phospholipids, increasing lipid packing density and stabilising the membrane

What happens in the absence of plasmalogens?

Causes demyelination, loss of myelin compaction, and axonal loss (shown in transgenic mice lacking plasmalogens)

What happens to amphipathic lipids in water?

They aggregate into bilayers due to the hydrophobic effect

How can lipid bilayers vary physically?

They can be more or less thick and fluid