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molecular basis of disease > neurodegenerative diseases > Flashcards

neurodegenerative diseases Flashcards

1
Q

Define neurodegeneration

A
  • neuro = relating to neurons

- degeneration = progressive loss

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2
Q

what are some basic details of neurodegenerative disease?

A
  • affect both CNS and PNS
  • associated with ageing
  • onset at earlier age = greater genetic contribution
  • highly heterogenous
  • conditions with overlapping phenotypes but distinct causes.
  • some diseases are inherently pleiotropic (produce more than one effect)
  • symptoms of same condition different in different individuals, eg: Parkinson’s disease
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3
Q

What are common features of neurodegenerative disease?

A

many follow a similar pattern:

  1. molecular impairment somewhere in the cell
  2. decreased transmission at synapse
  3. “dying back” of neurites (axons and/or dendrites)
  4. cell death
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4
Q

what is ‘achilles heel’

A

-distance between nucleus and axon terminal

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5
Q

what do neurodegenerative disease frequently involve?

A
  1. protein aggregration (protienpathies)
  2. lysosomal dysfunction
  3. mitochondrial dysfunction
  4. associated inflammation via activation of glia
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6
Q

What are features of Alzheimer’s disease?

A
  • most common cause of dementia
  • onset >65 y/o
  • incidence : 10% of ppl aged 65+ , 50% aged 85+
  • AD is NOT a normal part of aging it is a disease
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7
Q

What is dementia?

A
  • decline in memory and other cognitive functions that impair quality of life
  • impairments in dementia are distinct from ‘normal’ cognitive lapses.
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8
Q

What is the history of Alzheimer’s?

A
  • Alios Alzhiemers , German psychiatrist, 1906
  • initial psychiatric and pathological observation made in younger patients “pre-senile dementia”
  • pathology then found in older patients
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9
Q

What are pathological hallmarks pf AZ?

A
  1. brain shrunk
  2. proteinpathies :
    (a) amyloid plaques
    • extracellular protein aggregates
      • enriched in A beta peptides
        (b) neurofibrillary tangles
      • also called paired helical filaments
      • intracellular protein aggregates
      • enriched in tau protein
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10
Q

What is A beta?

A
  • A beta peptide is cleaved from a transmembrane protein called amyloid beta precursor protein (APP) by proteases (beta secretase and gamma secretase)
  • cleaved amines accumulate and form amyloid beta precursor protein.
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11
Q

What is the amyloid hypothesis?

A
  • mutations to three proteins involved in A beta peptide processing are known to cause rare early onset forms of alzheimer’s
  • APP = beta secreteaste
  • PSEN1 and PSEN2 both components of gamma secretase
  • since early 1990s “amyloid hypothesis of AD” states that A beta and amyloid plaques are the cause of AD
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12
Q

How does tau and neurofibrillary tangles lead to cell death?

A
  • tau normally binds microtubules in axons
  • hyperphosphorylated tau is displaced causing :
    tangles and destabilised microtubules
  • this leads to neuronal death
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13
Q

What are 3 main roles of microtubules in all post-mitotic cells?

A
  1. structural/shape of cell
  2. positioning of organelles
  3. motorways for transporting vesicular cargo
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14
Q

What is tau hypothesis?

A
  1. in typical late onset AD (ie: not genetic forms of AD), neurofibrillary tangles are:
    - seen before amyloid plaques
    - well correlated with cell death and progression
  2. suggests Tau is upstream A beta = tau hypothesis
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15
Q

What are other risk factors of Az?

A
  • down syndrome
  • gender
  • high BP, CVS, diabetes
  • low education
  • head imjury
  • smoking and drinking
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16
Q

What is the history of parkinsons disease (PD)?

A
  • first reported in 1817 by DR James
  • “shaking palsy”
  • identical symptoms identified by hungarian physician in 1690
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17
Q

What are symptoms of parkinsons?

A
  • movement disorder, with 4 cardinal features:
    1. resting tremor
    2. bradykinesia (slow movement)
    3. rigidity
    4. postural instability (fall over)
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18
Q

What are non motor symptoms?

A
  • > 90% of patients displat additional non-motor symptoms, including:
    -depression
  • loss of smell
  • sleep disorders
  • constipation
    less common :
  • dementia and other psychiatric complications.
19
Q

what are 2 pathological hallmarks of PD?

A
  1. loss of dopaminergic neurons of substania nigra
    -dopaminergic = neurons that produce the neurotransmitter dopamine
    -substantia nigra = “dark substance” part of basal ganglia in the midbrain
    => PD does NOT only affect dopaminergic neurons of the substansia nigra - other brain regions are also affected hence why we have other symptoms.
  2. Proteinopathy
    - lewy bodies :
    intracellular protein aggregates
    -enriched in a - synuclein protein
    -normal role of a synuclein is involved in NT release
20
Q

What differences can you observe in a normal brain section and PD brain section?

A
  1. normal section
    - neurons visible by eye due to expression of neuromelanin
  2. PD brain section
    - lack of pigmentation, shows loss of substantia nigra
21
Q

What are genetic causes of PD?

A

~10% of cases have clear genetic cause

  • 3 rough categories
    1. early/juvenile - onset recessive mitochondrial conditions
    2. late/later onset (usually) autosomal dominant PD
    3. Mutations that cause “PD-plus” conditions.
22
Q

What are features of early onset of mitochondrial parkinsons disease?

A
  • mitochondria have a finite lifespan due to oxidative stress
  • damaged mitochondria are selectively removed from the cell by “mitophagy” - autophagy of mitochondria
  • loss -of -function mutations in two proteins central to activating mitophagy - PINK1 and Parkin - cause EO PD.
  • loss of 3 other genes linked to mitochondrial stress responses also linked to early onset of PD.
23
Q

What are limitations of early onset mitochondrial PD?

A

-PD is distinct from late-onset sporadic PD (a whole different disease)

24
Q

What are examples of late onset genetic PD?

A
  1. SNCA (alpha- synuclein) gene amplification
  2. LRRK2 gain of function
  3. VPS35 gain of function
  4. GBA loss of function
25
Q

How are GBA and alpha - synuclein involved in PD?

A
  • GBA encodes GCase (beta -glucocerebrosidase) which is a lysosomal enzyme that breaks down alpha synuclein in the lysosome.
  • In healthy individuals GCase is transported/trafficked from glogi/ER into lysosome where alpha synuclein will degrade it.
  • accumlation of alpha synuclein leads to PD.
26
Q

What happens when a mutation leads to decrease in GCase?

A
  • less GCase transported into lysosome
  • less autophagy
  • lysosome degrades
  • accumulation of a-Syn
27
Q

What happens if you have increase in alpha synuclein due to sporadical mutation?

A
  • excess alpha synuclein inhibits the trasnport of GCase into lysosome
  • lysosome degrades
  • less alpha synuclein breakdown by lysosome so even more accumulation of alpha synuclein
28
Q

What is the pathogenic feed forward loop/positive loop?

A
  1. increased alpha synuclein inhibits GCase transport
  2. decreases GCase
  3. decreased lysosomal function
    so even less alpha synuclein degraded
29
Q

What is the pathogenic feed forward loop/positive loop?

A
  1. increased alpha synuclein inhibits GCase transport
  2. decreases GCase
  3. decreased lysosomal function
    so even less alpha synuclein degraded
    => cell death
30
Q

What is the role of other PD genes and how is it linked to lysosomes?

A
  • other genes play a role in processes involving lysosomes
  • consistently , autophagy is dysregulated in PD brains
  • problems in autophagy will also lead to mitochondrial dysfucntion (decreased mitophagy)
  • endocytosis pathway are area of research.
31
Q

What has GWAS of sporadic PD discovered?

A
  • risk genes , influence risk
  • also found many new PD genes
  • now believed as much as 30% of PD risk is genetic
32
Q

what is the link between Tau and PD?

A
  • reduce ability of cells to traffick vesicles make them more sensitive to PD/
33
Q

What are other risk factors?

A
  • gender (more common in men)
  • Red hair
  • Head injury
  • not smoking, not consuming alcohol
  • herbicides, pesticides , insecticides
  • exposure to metals
  • general anesthesia
34
Q

Define neuroinflamation

A
  • activation of the immune system within the nervous system

- in the brain, this principally means activation of microglia (astrocytes are also involved)

35
Q

What are features of ‘reactive microglia’?

A
  • amoeboid shape
  • more motile
  • production of cytokines
  • phagocytic
36
Q

How does neuroinflammation in neurodegeneration occur and amplify due to positive feedback loop?

A
  1. neurotoxin leads to neuronal damage
  2. this releases factors which activates microgilia (a-synuclein and other proteins are activators)
  3. reactive microglia releasese neurotoxic factors such as IL-1B, TNF-a, prostaglandins which trigger more cell damage and cell death(positive feedback)
37
Q

How can microglia be both protective and damaging?

A
  • reactive microglia can be protective of neurons or damaging
  • protective :
    =>anti-inflammatory eg TGFb
    => normal removal of unhealthy cells (ie. homeostasis)

-damaging
=> proinflamatory , eg: IL-1 , TNF - a
=> response to pathogens etc (damage to neurons = ‘collateral damage”)

38
Q

How does ageing and microglia relate?

A

-aging induces shift towards production of damaging reactive microglia, due to changes in microglia gene expression (neuroinflammaging)

39
Q

What are external triggers that activate microglia?

A
  • A beta
  • environmental triggers
  • pathogens
40
Q

Can neuroinflammation be the cause of Alzhiemers?

A
  • alzhiemers risk factors cause increased levels of circulating inflammatory cytokines
  • high BP, Cardiovascular disease, diabetes, smoking
  • effects can cross the blood -brain barrier
  • enough to cause AD
41
Q

How does gut inflammation cause damage in brain leading to PD?

A
  • Lewy body pathology in gut often preceded pathology in brain
  • Evidence that gut inflammation is sufficient to cause gut Lewy bodies
  • spread to brain via vagus nerve
42
Q

What are other effects of aging?

A
  • shortening of telomeres in adult stem cells
  • increased reactive oxygen species
  • other changes:
    =>altered Wnt signalling is a big focus in AD and PD
    => Wnts are neuroprotective and neuromodulatory
    => wnt/ beta- catenin is decreased in adult brain
    => Deregulated Wnts in developmental and geriatric neuro conditions.
43
Q

What are the challenges of studying neurodegenerative disease in clinic and research?

A
  • neurodegenerative diseases rarely manifest overt signs and symptoms until long after neurodegeneration has began.
    -> so early treatment is impossible without early diagnosis
    -> therapeutic challenge is considerable
    for CNS disorders , studies of affected tissue is very difficult until death.

molecular basis of disease (29 decks)

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