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Post-Midterm Biochem
Brain Metabolism
| Question | Answer |
|---|---|
| From which compounds does the brain derive its specialized, complex, and very-long chain lipids (Cerebrosides, Ganliosides, Plasmalogens, VLC-FAs)? | The essential fatty acids: A-linolenic acid (w3) and linoleic acid (w6) which can cross the blood-brain barrier because they are so small |
| A chain length longer than how many carbons is considered long? | 20C |
| Where are Very-long-chain fatty acids normally found? | Myelin |
| Compare the turnover rate of proteins and lipids in the brain to other tissues with differentiated cells? | The brain has a relatively high turnover rate compared to these other organs |
| What are the most abundant cell type of the nervous system? | Neuroglia (support cells) |
| What is the function of Astrocytes? | Support the blood-brain barrier |
| What is the function of Oligodendrocytes? | Production of the myelin sheath in the CNS, which can cover up to 40 nerve axons (as opposed to the Schwann cell which produces myelin for one axon in the PNS) |
| What is the function of Microglia? | Immune function |
| What is the major source of fuel for the brain in the fed state? | Glucose (to fuel aerobic respiration and glycolysis) |
| What is the major source of fuel for the brain in the fasting state (hours)? | Glucose (from glycogenolysis and gluconeogenesis) |
| What is the major source of fuel for the brain in the prolonged fasting state (2-3 days, aka starving)? | Ketone bodies |
| Can Ketone Bodies completely replace the the brain’s requirement for glucose? | No, some glucose is still required |
| What is ‘Glucose Sparing’? | The use of ketone bodies by the brain allows for a reduction in gluconeogenesis which gets its fuel from amino acids that are a result of muscle protein degradation |
| Is glucose uptake by the brain insulin-induced? | NO! The brain is constitutively taking up glucose, despite high or low levels of insulin |
| How do glucose and ketone bodies pass the blood brain barrier to enter the brain? | Specific facilitated diffusion channels (GLUT-1 and GLUT-3 for glucose, Monocarboxylate Transporter for ketone bodies) |
| What is the function of GLUT-1? | high affinity transport of glucose across endothelial membranes |
| What is the function of GLUT-3? | Transport of glucose into neurons |
| What is the function of GLUT-2? | High capacity, low affinity transport of glucose from intestinal cells to portal vein to Liver and B-cells |
| What is the function of the GLUT-4 transporter? | Insulin dependent transport of glucose into Skeletal, Cardiac, and Adipose tissue |
| What is the function of GLUT-5? | Transport of *Fructose* from intestinal luman into intestinal cells and testes |
| Describe the Monocarboxylate Transporter. | Transports Ketones along with Pyruvate, Lactate, and Acetate into the brain, functions more slowly than GLUT transporters, and its gene expression is upregulated during starvation |
| Aside from glucose and ketone bodies, what can the brain use as fuel? | Nothing, it has no stores of TAGs or Glycogen (No ‘fatty’ brain), it’s protein cannot be broken down to form the AAs for gluconeogenesis (the brain doesn’t use AA carbon skeletons for TCA), and fatty acids from TAGs can’t enter the brain (BBB stops them) |
| Give a brief description of the blood brain barrier. | Endothelial cells on systemic side, astrocytes on brain side separated by a *continuous* basement membrane (no sinuses or fenestrations). Endothelial cells have narrow intracellular spaces which are sealed together with tight junctions |
| What can pass through the blood brain barrier unassisted? | Small uncharged and non-polar molecules can freely and passively diffuse (O2, H2O, CO2, N2O, NH3, and many hydrophobic drugs like ethanol, nicotine, and diazepam) |
| Why may some hydrophobic drugs, like PHENOBARBITOL, pass through the blood brain barrier slower than expected? | Because they randomly bind with albumin in circulation before they reach the barrier |
| How do insulin and growth factors pass through the blood brain barrier? | Receptor-mediated endocytosis (which is protein specific) |
| How do essential fatty acids and vitamins pass through the blood brain barrier? | Specific Transporters |
| How do certain amino acids pass the blood brain barrier and which amino acids are these? | Large, neutral amino acids use a shared facilitative transporter to pass, these include branched chain amino acids (LIV), aromatic amino acids (TTP), as well as Met, His, and L-DOPA |
| When would the use of a shared facilitative transporter be problematic? | In PKU or MSUD, there are large quantities of Tryptophan and branched chain AAs in circulation, the passage of these molecules into the brain due to their high concentration would prevent the passage of other amino acids that are in normal concentrations. |
| Which amino acids cannot pass the blood brain barrier and why would they be blocked? | Amino acids that act as neurotransmitters (Glutamate, Glycine, GABA, Aspartate, and Dopamine), this is to keep the somatic pool separate from the neural pool (brain should use only what it synthesizes) |
| Which amino acid is actively transported out of the brain? | Glycine (build up can cause non-ketotic hyperglycinemia = mental retardation) Therefore Glycine is NOT transported INTO the brain. |
| How does the blood brain barrier affect treatment of Parkinsons Disease? | L-DOPA is given as a treatment for Parkinson’s so it can be converted to Dopamine after it crosses the BBB. Unfortunately, it’s often degraded to Dopamine BEFORE it crosses the BBB, preventing its passage. |
| What is given in conjunction with L-DOPA to preserve it while circulating from systemic to brain blood? | DOPA decarboxylase inhibitors, which prevent its degradation to Dopamine before it passes the BBB to make sure more L-DOPA gets across |
| What degrades somatic pools of Catecholamines and why? | MAO enzymes, this is to keep the somatic and neuronal pools of Catecholamines separate |
| What lipid class has a higher concentration in white matter (myelin) than grey matter? | Cerebrosides |
| Why is there a need for constant turnover of neuronal fatty acids, sphingolipids, phospholipids, and cholesterol? | The neuron myelin membrane is constantly losing mass via budding off of presynaptic vesicles filled with neurotransmitters and formation of postsynaptic endocytic vesicles for uptake of neurotransmitters. It must constantly be added to for maintenance. |
| What is the primary lipid component of myelin? | Cerebrosides (lipids in general form 70%, the majority, of the myelin sheath) |
| What are the 2 primary protein components of myelin and what is their function? | 1) Proteolipid protein and 2) Myelin Basic Protein (both aid in tight packing and stabilization of the myelin sheath) |
| Which non-protein aids in the tight packing of the myelin sheath? | Very-long-chain fatty acids (which stack on top of one another) |
| Describe Multiple Sclerosis. | Progressive formation of sclerotic plaques which destroys CNS myelin and slowing of neurotransmission. It’s caused by autoimmune reaction which is possibly triggered by viral infection. Causes weakness loss of coordination & vision, & can be fatal. |
| How are Neuropeptides synthesized (in general) and what is their function? | Neuropeptides are synthesized as large molecules but then cleaved to their smaller active form in the cell body and then travel down the axon, examples include Enkephalins, Endorphins, and Substance P |
| What is the function of Enkephalins & Endorphins? | Neuropeptides that act as natural opioids to mediate pain relief |
| What are the two gaseous neurotransmitters, how are they formed, and what do they activate? | Nitric Oxide (NO) from nitric oxide synthetase and Arginine and Carbon Monoxide (CO) from Heme Oxygenase, both stimulate the synthesis of cGMP |
| What are the 2 main excitatory amino acids neurotransmitters? | Glutamate and Aspartate |
| What are the 2 main inhibitory amino acid neurotransmitters? | Glycine and GABA |
| What main reaction is involved in the synthesis of neurotransmitters from amino acids and what cofactor is usually required? | Decarboxylation (from the a-carbon) which often requires PLP (Vitamin B6) |
| Which type of cells in the brain are responsible for conversion of glutamate and NH4+ to glutamine? | Astrocytes convert Glutamate + NH4+ -> Glutamine |
| Where does the NH4+ in the brain come from? | Deamination of an amino acid or transamination of an amino acid |
| What happens to glutamine in neurons on the brain? | Glutamine is converted to Glutamate then GABA (not A-ketoglutarate) |
| How is excess NH4+ transported out of the brain? | Glutamine |
| Can Glutamate, Aspartate, and Glycine be synthesized from glucose? | Yes, if there is a nitrogen source |
| Describe how GABA is recycled in the brain. | GABA is recycled by Glial cells (GABA -> Glial Cell uptake -> Glutamine -> transport to neurons -> converted back to Glutamate) |
| Which enzyme do Glial cells lack in reference to neurotransmitter synthesis? | Glutamate Decarboxylase |
| What is the GABA shunt? | An extra reaction by which the carbon skeleton of GABA (which comes from conversion to Glutamate) can be converted to Succinate for entry into the TCA cycle |
| What are 3 major ways Glutamate can be de novo synthesized in the brain? | 1) Deamination of Glutamine by Glutaminase, 2) Transamination of A-ketoglutarate with NH3 via PLP, and 3) Reductive amination of A-ketoglutarate + NH4+ + NADPH via Glutamate Dehydrogenase |
| What disease is associated with low GABA concentrations and what drug is used to treat this disorder? | Epilepsy, may be treated by GABA analogs or GABA reuptake inhibitors |
| How do Benzodiazepines (Valium) work? | Bind to GABA receptors and potentiate GABA for reduced anxiety |
| How does Phencyclidine (PCP) work? | It is an antagonist of of the NMDA (glutamate) receptor. It is a tranquilizer in animals but a hallucinogen in people. |
| What is the difference between an Agonist and an Antagonist? | Agonist = Activate Response, Antagonist = Inhibits Response |
| Where does the Choline in Acetylcholine come from? | Phospholipid synthesis or the diet |
| Which Phospholipid forms Phosphatidylcholine and what cofactors are necessary? | PC is formed from methylation of Phosphatidylethanolamine (PE) via SAM, THF, and Cobalamin (B12) (and Acetyl choline from glucose) |
| Which enzyme is responsible for acetylating choline to become acetylcholine? | Choline Acetyltransferase |
| Which enzyme breaks Acetylcholine down into Acetic Acid and Choline (think of post-synaptic clefts)? | Acetylcholinesterase |
| Aside from PDH complex and A-Ketoglutarate DH, what reaction requires TPP? | Branched chain amino dehydrogenase (to break branched chain a-keto acids down to Propionyl CoA) and Transketolase of PPP |
| What is another name for TPP? | Vitamin B1 (Thiamine Pyrophosphate) |
| What is the difference between Wernicke-Korsakoff Syndrome and Beri Beri Syndrome? | WK Syndrom is alcohol induced while Beri-Beri is diet-induced |
| What deficiency causes Wernicke-Korsakoff/BeriBeri? | Lack of TPP |
| Which 4 mammals are known to get Prion Disease (Transmissible Spongiform Encephalopathy) and what are the names of the prion disease in each? | Humans (Creutzfeldt-Jakob or Kuru), Sheep (Scrapie), Cattle (Mad Cow Disease, Bovine Spongiform Encephelopathy), and Squirrels (Mad Squirrel Disease, I guess – no name given) |
| What is the Prion disease called when BSE is passed to humans? | New Variant Creutzfeldt-Jakob (vCJD) |
| What are Prions? | Glycoproteins that may act as infectious agents when incorrectly folded |
| Is PrPc soluble and where is it found? | Yes, normal PrP (c) is soluble and it is found attached on the extracellular side of neuronal membranes |
| What is the function of PrPc? | It is unknown |
| What is meant by PrPsc being able to act as a template? | It catalytically converts PrPc to PrPsc |
| Is PrPsc soluble? | No it is insoluble and forms plaques on neurons making the brain look holey like a sponge (hence, ‘spongiform’) The B-sheet structure is what contributes to PrPsc’s inability to be degraded by normal processes |
| What is the difference in Secondary structure between PrPc and PrPsc? | PrPc = mostly A-helix, PrPsc = mostly B-sheets (this is a conformational shape change) |
| How does the secondary structure of PrPsc lead to disease? | It alters the Tertiary structure (protein folding). The misfolded protein acts as an infectious agent. |
| Which species can Prion disease be passed between? | Sheep to Cows, Cows to Humans, Squirrels to Humans, Bovine to Bovine and Human to Human (Kuru = cannibalism) |
| Can Humans get Scrapie? | No, humans have only been known to get prion disease from Cows and Squirrels |
| What type of event causes the misfolding of PrPc to become PrPsc? | A Sporadic, Spontaneous event that happens by chance (no known cause) |
| Can people have genetic predisposition to prion disease susceptibility? | Yes, but it does NOT mean they are going to get it |
| How are Prion Disease and Alzeheimer’s Disease similar? | They both involve plaque formation which causes degeneration (both involve B-sheets, neurodegeneration, progressive loss of memory/cognition, and neuron mitochondrial dysfunction too) |
| What develops in Alzeheimer’s disease? | Amyloid plaques which contained Amyloid-B-peptide with 42 amino acids |
| Where are the proteolytic fragments of Alzeheimer’s disease derived from? | B-amyloid precursor protein |
| Which proteolytic fragment from B-amyloid precursor protein (# of amino acids) is non-toxic and which is neurotoxic? | 42 = toxic, 40 = ok |
| What causes the 42-amino acid B-amyloid fragment to be toxic? | It contains mostly B-sheets which accumulates to form aggregates (can’t be degraded) and creates neurofibrillary (neuron) tangles which contain hyperphosphorylated ‘tau’ proteins. |
| What is the Tau protein? | A microtubule associated protein |
| What is the major risk factor for Alzeheimer’s Disease? | Age |
| Is acetylcholine and excitary or inhibitory neurotransmitter? | Excitatory |
| What vitamin is needed to generate SAM to make choline? | B12 |
| In what 3 ways can humans get Prion disease? | 1) Genetic (predisposition), 2) Infectious (eating contaminated foods), 3) Sporadic (a chance misfolding event) |
| Is their pinocytosis across the BBB? | No |
| What are the primary components of myelin? | Spingomyelin and Cerebrosides |
| Describe the formation of choline for acetylcholine. | PE --3SAM--> PC --PLD--> Choline (which can be acted by choline acetyltransferase) Phosphocholine is almost made in the reaction via PLC. |
Created by:
sprater16