Lecture Cycle 9- genetics of diseases

• What are the molecular mechanisms underlying Alzheimer's Disease?

  - formation of beta-amyloid plaques

  - formation of neurofibrillary tangles
• what type of neurons are affected in AD?

  cholinergic neurons
• What is the structure of neurons and how do they communicate at the synaptic cleft?

  - neurons receive chemical input through the dendrites

  - send signals to other neurons through the axon

  - communicate at the synaptic cleft through action potentials and neurotransmitters
• Why are cholinergic neurons downregulated in AD?

  - patients don't produce enough acetylcholine which leads to difficulty forming and recalling memories
• How is beta-amyloid plaque formed?

  - decreased expression of alpha-secretase = increased expression of beta secretase, resulting in more insoluble beta-amyloids

  - these beta-amyloid sheets stick together and form a plaque
• How are neurofibrillary tangles formed?
• What are the common drugs used to treat AD? What are their targets and functions?
• What are examples of genetic risk factors of AD?

  - Down Syndrome: increased expression on the APP protein

  - mutations in Presenilin 1 and 2: mutant gamma secretase produces larger [than 42] Abeta peptides which results in plaques

  - inheritance of Apo E4: not effective in removing aggregates
• What are some potential AD drugs that are currently in development?
• Why do cancers have genetic heterogeneity?

  each cell in a tumor expresses different heterogeneity, this is what makes cancer hard to treat
• What is the difference between inter-tumoral heterogeneity and intra-tumoral heterogeneity?
• What is the process of clonal evolution of cancer?
• How do certain cancer cells become resistant to drug treatment which leads to relapse?

  most aggressive clone will relapse, resultin in a different heterogeneity
• What is the difference between driver mutations vs passenger mutations?

  - driver: push to proliferate, these lead to cancer

  - passenger: no functional effects
• How do endogenous DNA damage and environmental exposures lead to DNA damage, mutator phenotype, chemotherapy resistance?
• What is the difference between proto-oncogenes (like RTK) and tumor-suppressor genes (like p53) and how can they lead to cancer progression?

  - proto-oncogenes: growth factor receptors; mutation causes conformation of growth factor receptors to change, resulting in them remaining active

  - tumor suppressor genes: cell cycle checkpoint and DNA repair; mutation to the DNA binding domain inhibits the signals of apoptosis
• What is the role of cancer stem cells in cancer progression and therapy?

  target cancer stem cells in therapy to get tumor regression; tumore relapse occurs because cancer stem cells are resistant to chemo therapy
• What is the experiment in mice to prove about oncogenesis?


  - separated cancer stem cells from normal cancer cells

  - injected each type of cell into mice

  - the mouse injected with the cancer stem cells resulted in tumor growth, maintaining the cancer phenotype