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Winter 2023 - Biology > Cycle 9: Genetics of Diseases > Flashcards

Cycle 9: Genetics of Diseases Flashcards

1
Q

What are the molecular mechanisms underlying Alzheimer’s Disease?

A

neurodegenerative: loss/deterioration of neurons in the brain
–> progressive - irreversible

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2
Q

What are the main symptoms of Alzheimer’s disease?

A
  • loss of memories
  • loss of cognitive function
  • can be early onset (early in life – usually familial/genetic predisposition) or late onset (more common, in elderly)
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3
Q

Where does AD start?

A

neurodegeneration starts in hippocampus which is involved in storing memories, recalling and making new memories and then radiates outwards

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4
Q

What are the 3 ways to get AD?

A
  1. Cholinergic neurons (neurons for memory and learning)
  2. Beta-amyloid Plaques
  3. Neurofibrillary tangles
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5
Q

What are the structures of neurons? What does the axon do?

A
  • cell body/soma has all organelles and connects to dendrites (receive neurotransmitter) and axon carries signal and axon terminal (release neurotransmitter)

axon carries signal, neurotransmitter and molecules. axon has microtubules form axon structure. microtubules structural protein: TAU

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6
Q

How do neurons communicate at the synaptic cleft?

A

with neurotransmitter

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7
Q

How do cholinergic neurons work?Why are cholinergic neurons down-regulated in AD?

A
  1. Mitochondria makes Acetyl CoA
  2. Acetyl CoA + Choline makes Acetyl choline with enzyme CHOLINE ACETYL TRANSFERASE
  3. Acetylcholine binds to post synaptic cholinergic receptor activating receptor which sends signal transduction (causes neuron to function – in this case recall something)
  4. Enzyme ACETYLCHOLINESTERASE on post synaptic enzyme breaks ACh back into choline and acetate bc if ACh binds on receptor for too long this is overstimulation
  5. choline and acetate goes back into presynaptic neuron through receptor

In AD, CAT noT produced, or only in small amounts so Acetylcholine is not made so no activation of receptor = no recall/memory function

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8
Q

What are the normal molecular mechanisms of APP degredation?

A

NORMAL - common
- alpha secretase cuts APP at outer location and cut sequence pushed out of neuron
- gamma secretase cuts APP in top segment
- two soluble segments

NORMAL - uncommon
- beta secretase cut APP tail
- gamma secretase cuts APP top and outer segment called amyloid-beta
- insoluble segment 36-42 aa peptides (if 42 = AD) need to be cleared by enzymes microglia, astrocytes and apolipoprotein E.

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9
Q

What is APP?

A

amyloid precursor protein - on neuron membrane role in neuron functioning - that has a turnover rate/need to be replaced and when broken down, each segment has a role

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10
Q

What is the molecular mechanism of beta-amyloid plaque formation?

A
  • increase in production of insoluble segments bc beta secretase is highly expressed
  • not enough clearance by enzymes
  • amyloid beta’s structure makes it sticky causing it to aggregate when pushed out of cell forming plaque
  • causes great activation of immune cells (astrocytes and microglia) in brain leading to inflammation and damage to neurons bc plaque is an unknown think
  • plaques also block communication in synaptic cleft by sticking to synapse
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11
Q

What are the components of gamma secretase?

A

protein complex including presenilin-1
- that protein is the catalytic unit/cutting of gamma secretase
- also the protein that gets mutated and passed on (leads to familial AD)

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12
Q

How do astrocytes and microglia function in immune response?

A
  1. amyloid beta forms aggregate/plaque
  2. resting microglia becomes activated microglia
  3. activated microglia releases cytokines
  4. astrocyte detects cytokines
  5. activated astrocytes release apolipoprotein E (protein with lipidation - surrounded by lipid)
  6. Apo E gets rid of AB aggregate
  7. astrocyte releases glutamate as a byproduct (in high amts in AD when trying to get rid of plaque)
  8. glutamate (neurotransmitter) activates its neurons – neuron hyper-stimulated and dies
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13
Q

How do ACETYLCHOLINESTERASE inhibitors (drug) work? What does it target?

A

inhibit ACETYLCHOLINESTERASE from functioning so that ACh stays bound to receptor and in synapse so that ACh is not broken down bc patients need stimulation of receptor for memory

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14
Q

How does the NMDA Antagonist drug work? What does it target?

A
  1. glutamate binds to NMDAR receptor on post synaptic cell causing over stimulation
  2. NMDA antagonist binds to NMDA receptor so that glutamate can’t
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15
Q

What is the molecular mechanism of neurofibrillary tangle formation?

A
  1. Tau is a protein that hold microtubules in axon of neuron together
  2. proteins in a cell can be phosphorylated or not – add too many phosphate groups = hyperphosphorylation - doesn’t function
  3. when hyperphosphorylated TAU proteins – TAU doesn’t function = microtubules fall apart
  4. TAU protein aggregate together forming tangles
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16
Q

What are the genetic risk factors of AD?

A
  1. Down syndrome - trisomy 21
    - APP gene coded on chromosome 21
    - increased APP expression - increased risk of early onset
  2. Mutations in Presenilin 1 & 2
    - presenilin 1 coded on chromosome 14 and presenilin 2 on chromosome 1
    - found in familial AD = early onset of AD
    - mutant gamma secretase produces larger AB peptides (42aa) leading to more aggregates
  3. Inheritance of Apo E4 (variant of Apo E)
    - Apo E coded on chromosome 19
    - Apo E2 is rare
    - Apo E3 most common variant in population and eddicient at removing AB aggregates
    - Apo E4 not effective at remosting AP aggregates. Autosomal dominant form of inherihance
17
Q

know that there are many potential AD drugs in the developmenal pipeline.

A
  1. Disease-modifying drugs
  2. symptom reducing drugs
  3. disease-modifying small molecule
18
Q

What does it mean for cancer to have genetic heterogeneity?

A
  • use single cell genome sequencing
  • mutations are different between different cells
19
Q

What is the difference between inter-tumoral heterogeneity and intra-tumoral heterogeneity?

A

inter-tumoral heterogeneity
- difference between different people’s tumour cells mutations of the same type of cancer
- personalied medicine

intra-tumoral heterogeneity
- single cell genome sequencing – difference between cells in same person
- precision medicine

20
Q

What are the characteristics of oncogenic (cancer) cells)?

A
  1. proliferation - divide
  2. anti-apoptosis - no cell death
  3. growth pathways - certain size b4 division
  4. motility - move (same organ)
  5. invasiveness
  6. angiogenesis - making more blood vessel for nutrients by extending existing blood vessels
  7. escape immune surveillance - previous characteristics makes in a foreign cell which immune system would attack
21
Q

What is clonal evolution of cancer?

A
  1. every mutation gives proliferation advantage causing increased growth
    – clonal expansion - causes cells to obtain all oncogenic characteristics
  • even if cancer causing mutation is present, it may not cause it bc it requires a different gene mutation to occur first
22
Q

How do certain cancer cells become resistant to drug treatment which leads to relapse?

A
  • more mutations to precursor mutation
    0 chemotherapy is the most popular way to
23
Q

Driver mutations

A
  • causes oncogenesis
  • concerned growth advantage and lead to all 7 characteristics
  • positively selected in the microenvironment of the tissue in which the cancer arises
  • often required for maintenance of the first cancer (remove driver, may remove cancer)
  • 2-5 driver mutations to get cancer depending on how many mutations needed to get all 7 characteristics
24
Q

passenger mutations?

A
  • not selected for by cancer cell
  • not conferred growth advantage
    not contributed to cancer development
  • mutations found within cancer genome bc somatic mutations without functional consequences often occur during cell division (biologically inert somatic mutations)
  • starts in gestation
25
Q

How does endogenous DNA damage and environmental exposures lead to DNA damage and mutator phenotype and chemotherapy resistance?

A

endogenous - inside cell DNA damage

exogenous - external environment mutation

mutator phenotype - higher chance of mutating another gene bc some have already been mutated and this introduced more abnormal regulation in cell

26
Q

What is the difference between proto-oncogenes (for example RTK) and tumor-suppressor genes (for example p53) leading to cancer progression?

A

both driver mutations

normal genes in body that may cause cancer when mutated

proto-oncogenes - RTK - growth factor receptor - binds to growth factor causing RTK to change conformation when phosphorylated signals cell to grow
–> cancer cells causing receptor to always to be active

tumour-suppressor gene - p53 - transcription factor - usually prevents cells from dividing if there is a mutation
–> cancer cells mutate p53 in DNA binding domain (not transcription activation domain)

27
Q

What is the role of cancer stem cells in cancer progression and therapy?

A
  • cancer originating in a niche where clone is a stem cell
  • cancerous cells are STEM cells
    (stem cells self-renew the progenitors)
  • not all types of cancer can originate from a stem cell
  • stem cells (and cancer stem cells) proliferate slowly
  • chemotherapy targets rapidly proliferating cancer cells but stem cells do not proliferate quickly! –> chemo resistant! – causes relapse - kill rapidly proliferating cells but not stem cells
28
Q

What was experiment in mice to prove that cancer stem cells drive oncogenesis?

A
  1. divide cancer stem cells and normal cancer cells by cell surface markers
  2. cancer stem cells have high CD44 and low CD24 and normal cancer cells high CD44 and high CD24
  3. inject 20000 cancer cells in mouse –> NO TUMOR
  4. inject 200 cancer stem cells in mouse
    –> TUMOR

–> stem cells drive oncogenesis, normal cancer cells need Sten cells to maintain tumor mass

** target only stem cell - causes tumour shrinkage and regression

** unspecific therapy – tumour shrinkage and relapse

Winter 2023 - Biology (11 decks)

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