Cycle 9: Genetics of Diseases

Cards (37)

  • 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