Cycle 9: Genetics of Diseases

• What is Alzheimer's Disease


  Progressive and fatal, neurodegenerative disease, most common cause of dementia, starts in the hippocampus and spreads outwards
• What do you lose to Alzheimer's


  Loss of neurons, memories, and cognitive function (irreversible)
• Dendrites


  Receives signals from surrounding neurons
• Soma


  Cell body with organelles
• Axon


  Long extension of the cell, carries neurotransmitters, nutrients and signals from the presynaptic neuron to the axon terminal. Has a myelin sheath
• Synaptic cleft


  Gap where the presynaptic neuron axon terminals meet postsynaptic neuron dendrites
• Microtubules


  Essential for nutrient transport and structural support. Stabilized by tau proteins
• Cholinergic neurons release a neurotransmitter called


  Acetylcholine = acetyl-CoA + choline
• What is Choline acetyl transferase (CAT)


  An enzyme that makes acetylcholine
• What is acetylcholinesterase


  An enzyme that breaks down acetylcholine.
• In Alzheimer's patients(cholinergic neuron degeneration)


  The pathway is downregulated  (less CAT, less acetylcholine) 
• Acetylcholinesterase inhibitors


  Inhibit the enzyme that breaks down acetylcholine so that it is degraded less frequently and is active longer
• Amyloid precursor protein (APP)


  Transmembrane protein that plays an important role in the function, maintenance, and repair of neurons
• Normal B-Amyloid Plaque processes


  More alpha secretase than beta secretase. Normal production and clearance of amyloid beta. Gamma secretase cuts to form a soluble peptide
• B-Amyloid Plaque processes in Alzheimer's patients


  More beta secretase than alpha secretase. Gamma secretase cuts to form a longer peptide. HIgher production of insoluble amyloid beta and lower clearance of amyloid beta both lead to plaques
• How do amyloid beta plaques cause brain deterioration? 


  Excessive release of toxic cytokines → inflammatory response → neuron loss. Overactivation of microglial cells and astrocytes → build-up of glutamate → neuron damage. Crowd synaptic clefts → block receptors → decreased communication between neurons
• NMDA Antagonists


  Inhibit NMDA receptors on the postsynaptic neuron so that excess glutamate has no effect on neurons. Relieves symptoms, but does not cure disease
• Neurofibrillary tangles (TAU)


  Have microtubules (a key structure that allow molecules/ nutrients from the stroma to reach the axon), and TAU proteins (forms subunits in microtubules to hold them together)
• In Alzheimer's patients there are 


  Hyperphosphorylated TAU (many phosphate groups attached to TAU, causing tangles). Microtubules falling apart and fibrillary tangles formed will both contribute to neuron death.
• Down Syndrome


  Extra APP (B-Amyloid Plaques) gene on extra chromosome 21
• ApoE4


  Less effective at removing amyloid aggregates
• Intertumoral Heterogeneity (between individuals)


  Genetic differences between different individuals with the same type of cancer, personalized medicine
• Intratumoral Heterogeneity (within a single patient)

  Genetic differences among cells of the same tumor within the same individual, precision medicine
• Single cell genome sequencing


  The genome of each individual cell within a tumour splice can be sequenced
• Clonal Evolution


  Mutations that encourage proliferation accumulate, eventually leading to uncontrollable cell growth
• Clonal expansion and genetic heterogeneity create


  Obstacles for treatment, drug resistance
• Oncogenic cells will ...


  Proliferate, avoid apoptosis, grow, move and invade, create new blood vessels (angiogenesis), evade body's immune response
• Driver Mutations


  Contribute to cancer development. Required for causation, progression and maintenance of cancer
• Passenger Mutations


  Do not contribute to cancer development. Normal mutation processes. No growth advantage (no selection)
• Nature (2009): 2-5 driver mutations to


  Classify as cancer
• Driver mutations fall under two categories


  Proto -oncogenes and tumour suppressor genes (both normally present in cells, driver mutations tend to be present because they are more likely to lead to cancer progression)
• Proto -oncogenes


  Mutations in genes are likely to lead to oncogenic phenotype
• Tumour suppressor genes


  Mutation prevents this gene from performing its normal job with suppressing tumorigenic cells (ex: affects cell cycle checkpoints)
• p53


  The most common driver mutation (over 60% of cancers involve this mutation), guardian of the genome
• What is a transcription factor?

  Proteins that help turn specific genes on or off by binding to nearby DNA
• How are cancer stem cells different from normal stem cells?

  Cancer stem cells divide slowly, but non-cancer stem cells divide rapidly (resistant to chemotherapy, results in tumor relapse as persistent cancer stem cell remains)
• Cancer stem cell specific therapy


  Targets the actual cancer stem cell that sustains the tumor, results in tumor regression → new direction of therapy