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Molecular Basis Of Disease > Neurodegenerative Diseases > Flashcards

Neurodegenerative Diseases Flashcards

1
Q

Define neurogeneration

A

Progressive loss of neurons

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2
Q

Define Neurodegenerative disease

A

Any disease caused by neurodegeneration

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3
Q

What are some patterns with neurogenerative diseases based on the age of onset?

A

Earlier age of onset = greater genetic contribution

Later age of onset = more likely a sporadic

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4
Q

What are the characteristics of neurodegenerative diseases?

A

Highly heterogenous
- some disease names are really umbrella terms
- some diseases are inherently pleiotropic

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5
Q

What are the common features of neurodegenration?

A
  1. Molecular impairment somewhere in the cell
  2. Decreased transmission at synapse
  3. “Dying back” of neurites (axons or dendrites)
  4. Cell death
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6
Q

What is defined as a neurones “Achilles heal”?

A

Distance between the axon terminal and nucleus

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7
Q

What do neurodegenerative diseases frequently involve?

A

Protein aggregation

Lysosomal dysfunction

Mitochondrial dysfunction

Associated inflammation via activation of Glia

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8
Q

Why is it hard to treat and research neurodegenerative diseases?

A

They rarely manifest overt signs and symptoms until long after neurodegeneration has begun
- early treatment is impossible without early diagnosis
- therapeutic challenge is considerable

Studies of affected tire is very difficult until death

Remain incurable

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9
Q

What is Alzheimer’s?

A

Most common neurodegenerative disease and most common cause of dementia

Onset usually >65

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10
Q

What is dementia?

A

A decline in memory and other cognitive function that impair quality of life.

Eg. Lost in own neighbourhood or recognise faces of family members

NOT NORMAL AGEING

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11
Q

What are the pathological hallmarks of Alzheimer’s?

A

Brain shrinkage

Proteinopathies

  • amyloid plaques
    (Extracellular protein aggregates)
    (Enriched in A-beta peptides)
  • neurofibrillary tangles /helical filaments
    (Intracellular protein aggregates)
    (Enriched in Tau protein)
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12
Q

What is A-beta?

A

Peptide cleaved from a transmembrane protein called amyloid beta precursor protein (APP) by proteases

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13
Q

What mutation involved in A-beta peptide processing are thought to cause rare early onset forms of Alzheimer’s?

A

APP gene

PSEN 1 gene - presenile 1

PSEN2 gene - presenile 2

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14
Q

What is tau?

A

A protien that normally binds to axons in microtubules

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15
Q

What is the function of tau?

A

Hyperphosphorylated and becomes displaced

  • forms tangles
  • forms destabilised microtubules (as it detaches)
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16
Q

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

A
  • structure/shape of cell
  • positioning of organelles
  • motorways for transporting vesicular cargo
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17
Q

In typical late onset Alzheimer’s disease what is observed?

A
  • neurofibrillary tangles are seen before amyloid plaques
  • neurofibrillary tangles are well correlated with cell death and progression
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18
Q

What is the Tau hypothesis?

A

Suggests Tau is upstream A-Beta

19
Q

Why are scientists debating weather amyloid or Tau have a bigger contribution to Alzheimer’s?

A
  • more evidence for amyloid HOWEVER therapies inhibiting A beta aggregation haven’t worked
    So far
  • tangles and plaques may be red herrings (could be pathogenic, or by standers or even protective)
20
Q

What are risk factors of developing Alzheimer’s?

A

Down syndrome (APP on chromosome 21)

Gender (more in women)

High BP, cardiovascular disease, diabetes

Low education

Head injury

Smoking and drinking

  • only a small genetic risk condition for late onset
21
Q

What is Parkinson’s disease?

A

Second most common neurodegenerative disease

A movement disorder

Usually 60-65 years

22
Q

What are the motor symptoms of Parkinson’s?

A
  • resting Tremor (trembling hands and feet)
  • Bradykinesia (slow movement)
  • Rigidity
  • postural instability (fall over)
23
Q

What are the non motor symptoms of Parkinson’s disease?

A

Depression + Anxiety

Loss of smell

Sleep disorders

Constipation

Dementic

24
Q

What are the pathological hallmarks of Parkinson’s?

A

Loss of dopaminergic neurons of the substantial nigra (part of basal ganglia in midbrain).

Proteinopathy - Lewy bodies
Intracellular protein aggregates
Enriched in a synuclein protein

25
Q

Are Lewy bodies pathogenic in Parkinson’s?

A

No but the increased a-synulein protein is

26
Q

What genes are associated with causing Parkinson’s?

A

Early/Juvenile-onset recessive mitochondrial conditions

Late/later onset autosomal dominant PD

Mutations that cause “PD-plus” conditions

27
Q

Describe what occurs during early onset mitochondrial PD?

A

Mitochondria have a finite lifespan due to oxidative stress

Loss of function mutation in two proteins central to activating mitophagy - PINK1 and Parkin

Limitation: this PD is distinct from late onset sporadic Parkinson’s (a whole different disease?)

28
Q

Describe what occurs during late onset genetic PD?

A

S-synuclein Gene amplification
- confirms a-synuclein is pathogen and a cause of Parkinson’s

LRRK2 gain of function

VPS35 gain of function

GBA loss of function

VERY SIMILAR TO SPORADIC PARKINSON’S

29
Q

Describe the correlation of GBA and alpha-synuclein.

A

GBA encodes GCase, a lysosomal enzyme

Alpha-synulein is degraded in the lysosome

And they’re connected - LESS ACTIVE GCase means accumulation of alpha-synuclein

OR alpha-synuclein inhibits the activation of GCase

30
Q

What happens in the pathogenic feed forward loop of Parkinson’s?

A

Increased alpha-synuclein

Decreased GCase

Decreased lysosomal function

31
Q

What are risk genes of Parkinson’s?

A

Has shown many “cause genes” influence risk

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

More neurofibrillary tangles are found in people with brains of LRRK2 PD

Microtubules disruption long implicated in PD

May not be enough to cause Parkinson’s by itself

33
Q

What are the risk factors of Parkinson’s?

A

Gender (more in men)

Red hair. (X2 risk)

Head injury

Not smoking, not consuming caffeine,

Herbicides, pesticides, insecticides

Exposure to metals

General anaesthesia

34
Q

What is neuroinflammation?

A

Activation of immune system within the nervous system.

Activation of microglia in the brain

35
Q

What is the structure and function of “reactive” glia?

A

Ameboid shape

More motile

Production of cytokines

Eventually become phacogytic

36
Q

Describe how neurodegeneration can cause neuroinflammation.

A
  1. A neurotoxic insult (injury, gene mutations, toxins) cause neuronal death/damage
  2. Microganglial activators (alpha-synuclein) are released from the damaged neurones
  3. This activates micro glia
  4. Micro glia then release neurotoxic factors (IL-1B, prostaglandins, and TNF-alpha )
37
Q

How can reactive micro glia be protective?

A
  • anti inflammatory cytokines released (TGF beta)
  • normal removal of unhealthy cells (homeostasis)
38
Q

How can micro glia be damaging?

A
  • pro inflammatory cytokines released (TNF alpha, IL-1)
  • response to pathogens (damage to neurones = collateral damage)
39
Q

What is neuroflammaging?

A

Ageing induces a shift toward productions of damaging micro glia due to changes in micro glial gene expression.

40
Q

What are some external triggers of neural glia activation?

A

A beta

Enviomental toxins

Pathogens

41
Q

Can neuroinflammation cause Alzheimer’s?

A

Many Alzheimer’s risk factors cause raised levels of inflammation

In principal, effects can cross the blood brain barrier

Doesn’t cause Alzheimer’s

42
Q

Explain the theory that Parkinson’s cause be caused from gut to brain signalling

A

Evidence suggests that gut inflammation is sufficient to cause gut Lewy bodies

Spread to vein by vagus nerve?

Could be a cause for increased constipation with Parkinson’s

43
Q

What are other effects of aging on neurodegeneration?

A

Shortening of telomeres in adult stem cells

Increased reactive oxygen species

Other changes in gene expression
- altered Wnt signalling is a big focus in AD and PD
- Wnts are neuroprotective and neuromodulatory
- Wnt/beta catenin in signalling pathway is decreased in adult brain
- Deregulated Wnts in developmental and geriatric

Molecular Basis Of Disease (32 decks)

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