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Molecular Basis of Disease - SGUL (Sem 4) > Neurodegenerative Diseases > Flashcards

Neurodegenerative Diseases Flashcards

1
Q

Define neurodegenration

A

neuro (relating to neurons) + degeneration (progressive loss)

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2
Q

What is a neurodegenerative disease

A

any disease caused by neurodegeneration

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3
Q

What are some features of neurodegenerative diseases

A

Affect the CNS or PNS (or both)

Begin at any stage of life:
- The most common ones are associated with ageing
- Rarer types of neurodegenerative disease start in childhood or even from birth
- Earlier age of onset = greater genetic contribution
- Later age of onset = more likely a sporadic (or idiopathic) disease

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4
Q

Why are neurodegenerative diseases highly heterogeneous

A
  • Some disease names are really umbrella terms. Conditions with overlapping phenotypes, but distinct causes (e.g. at least 25 types of SCA from mutations in different genes)
  • Some diseases are inherently pleiotropic symptoms manifest differently in different people e.g. Parkinson’s disease symptoms unique to individual)
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5
Q

what are some common features of AD?

A

Many follow a similar pattern:

  • Molecular impairment somewhere in the cell
  • Decreased transmission at synapse
  • “Dying back” of neurites (axons and/or dendrites)
  • Cell death

Frequently involve:

  • Protein aggregation (“proteinopathies”)
  • Lysosomal dysfunction
  • Mitochondrial dysfunction
  • Associated inflammation via activation of glia
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6
Q

What are the clinical and research challenges

A
  • Neurodegenerative diseases rarely manifest overt signs and symptoms until long after neurodegeneration has begun

Early treatment is impossible without early diagnosis
The therapeutic challenge is considerable

  • For CNS disorders, studies of affected tissue is very difficult until death
    Advanced brain pathology is of little help to understanding the causes
  • Neurodegenerative diseases remain incurable
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7
Q

What is Alzheimer’s disease

A
  • The most common neurodegenerative disease and the most common cause of dementia
  • Onset is usually >65 years of age, but ~10% are “early onset” starting ~30s onwards
  • Incidence:
    10% of people aged 65+
    50% of people aged 85+
  • AND is NOT a normal part of ageing, it is a disease
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8
Q

What is dementia

A
  • 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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9
Q

How was Alzheimers discovered

A
  • First described by Alois Alzheimer, a German psychiatrist and neuroanatomist, in 1906/7
  • Initial psychiatric and pathological observations made in younger patients
    “Pre-senile dementia”
  • Pathology then found to be widespread in older patients
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10
Q

What is the 1st pathological hallmark of Alzheimer’s

A

Brain shrinkage

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11
Q

What is the 2nd pathological hallmark of Alzheimer’s

A

Proteinopathies:

  • Amyloid plaques
    Extracellular protein aggregates
    Enriched in Aβ peptides
  • Neurofibrillary tangles
    Also called paired helical filaments
    Intracellular protein aggregates
    Enriched in Tau protein
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12
Q

Describe Amyloid plaque formation

A

Aβ peptide is cleaved from a transmembrane protein called amyloid beta precursor protein (APP) by proteases:
- B-secretase
- Y-secretase

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13
Q

what is the amyloid hypothesis?

A
  • Mutations to three proteins involved in Aβ peptide processing are known to cause rare early-onset forms of Alzheimer’s
    APP
    PSEN1
    PSEN2

PSEN1/2 both are components of y-secretase

  • Since early 1990’s “Amyloid hypothesis of AD”, which states that Aβ and/or amyloid plaques are the cause of AD
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14
Q

Explain tau and the formation of neurofibrillary tangles

A
  • Tau normally binds microtubules in axons
  • Hyperphosphorylated tau is displaced causing:
    Tangles
    Destabilised microtubules
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15
Q

what is the importance of microtubules in neurites

A

In all post-mitotic cells, microtubules have 3 main roles:

  • Structure/shape of cell
  • Positioning of organelles
  • Motorways for transporting vesicular cargo
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16
Q

What is the Tau hypothesis

A
  • In typical late onset AD (i.e. not genetic forms of AD), neurofibrillary tangles are:
    Seen before amyloid plaques
    Well correlated with cell death and progression
  • Suggests Tau is upstream Aβ = Tau hypothesis
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17
Q

What causes AD, amyloid or Tau

A
  • Probably more evidence for amyloid, but…
    Therapies based on inhibiting Aβ aggregation so far haven’t worked
  • Tangles and plaques may be red herrings
    Are they pathogenic or by-standers? Or even protective?
    Oligomeric forms of Aβ and tau are more likely to be pathogenic

Could both be downstream of other factors?

18
Q

What are the other risk factors of AD

A
  • Down syndrome (APP is on chromosome 21)
  • Gender (more common in women)
  • High BP, Cardiovascular disease, Diabetes
  • Low education
  • Head injury
  • Smoking and drinking
  • Only a small genetic risk contribution for late-onset AD (APOE gene status most significant)
19
Q

What is Parkinson’s disease

A
  • The second most common neurodegenerative disease
  • Onset is usually 60-65 years of age, but ~10% start before 45 years of age
  • Lifetime risk:
    Males ~2%
    Females ~1.3%
  • Like AD, Parkinson’s disease is incurable
20
Q

What is the history of PD

A
  • ‘First’ reported in 1817 by Dr James Parkinson, an East London physician
    “Shaking palsy”
  • Identical symptoms described by a Hungarian physician, Ferenc Pápai Páriz, in 1690.
  • However, the similar observations stretch back to ancient Egypt.
21
Q

What are the symptoms of PD

A
  • A movement disorder with four cardinal features
    1) Resting tremor
    2) Bradykinesia
    3) Rigidity
    4) Postural instability
22
Q

what are the non-motor symptoms of PD

A

90% of patients display additional non-motor symptoms, including:
- Depression & Anxiety
- Loss of smell
- Sleep disorders
- Constipation
These are more common

  • Dementia
  • Other psychiatric complications
    Less common symptoms
23
Q

what are one pathological hallmarks of PD

A
  • Loss of dopaminergic neurone of the substation nigra
  • Lack of pigmentation shows loss of substantia nigra
24
Q

What is another pathological hallmark of PD

A

Proteinopathy

  • Lewy bodies
    Intracellular protein aggregates
    Enriched in α-synuclein protein
  • Normal role of α-synuclein is poorly understood (involved in neurotransmitter release)
  • Lewy bodies not pathogenic, but ↑ α-synuclein is
25
Q

What are the genetic causes of PD

A

10% of cases have a clear genetic cause

Three rough categories:

  • Early/Juvenile-onset recessive mitochondrial conditions
  • Late/later-onset (usually) autosomal dominant PD
  • Mutations that cause “PD-plus” conditions
26
Q

Explain early onset mitochondrial PD

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
    Mutations in at least 3 other genes linked to mitochondrial stress responses also linked to EO PD
  • Limitation: this PD is distinct from late-onset sporadic PD (whole different disease?)
27
Q

Explain late-onset genetic PD

A
  • Some genetic causes found from kindred studies (like EO PD), but more limited, including:
  • SNCA (α-synuclein) gene amplification
    Confirms that α-synuclein is pathogenic
  • LRRK2 gain-of-function
  • VPS35 gain-of-function
  • GBA loss-of-function
28
Q

How is GBA & α-SYNUCLEIN connected

A
  • GBA encodes GCase (β-glucocerebrosidase ),a lysosomal enzyme
  • α-synuclein is degraded in the lysosome
29
Q

Explain the mechanism how GBA & α-SYNUCLEIN are linked

A

Normally α-SYNUCLEIN is broken down in lysosomes by GCase which is transported in from Golgi/ER

When there is reduced GCase there is less degradation of a-syn.

There is increased a-syn which results is the formation of lewy bodies

30
Q

Explain the pathogenic feed-forward loop

A

Increases a-syn can inhibit the transport of Gcase into lysosomes which leads to less breakdown of a-syn. Further feeds into the cycle

31
Q

What is the link between autophagy and PD

A
  • Other PD genes play roles in processes involving lysosomes
  • Consistently, autophagy is dysregulated in PD brains.
  • Problems in autophagy will also lead to mitochondrial dysfunction (↓ mitophagy)
  • Endocytic pathways are a big focus in PD research
32
Q

What are risk genes in PD

A
  • Risk genes has shown many “cause genes” also influence risk
  • Also found many new PD genes
  • Now believed as much as 30% of PD risk is genetic
33
Q

How is Tau linked to PD

A
  • Linkage of MAPT to PD was a big surprise
  • Neurofibrillary tangles can be found in PD brains (even in the same cells as Lewy bodies), but not to any great extent

However:

  • More NFTs in brains of LRRK2 PD
  • Microtubule disruption long implicated in PD
34
Q

What are the other risk factors of PD

A
  • Gender (more common in men)
  • Red hair (~2x risk)
  • Head injury
  • Not smoking, not consuming caffeine
  • Herbicides, pesticides, insecticides
  • Exposure to metals (i.e. welder)
  • General anaesthesia
35
Q

What is neuroimmflamation

A

Activation of the immune system within the nervous system

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

36
Q

How are microglia ‘reactive”

A
  • Amoeboid shape
  • More motile
  • Production of cytokines
  • (Eventually) Phagocytic
37
Q

How is neurodegeneration mediated by neuroinflammation

A
  • A neurone experiences injury, toxins or gene mutations
  • Microglial activators such as a-syn and other protein are released from neurones which activate microglia
  • Neurotoxic factors are released from microglia
  • The neurone dies
38
Q

How is aging and microglia related

A

Reactive microglia can be protective of neurons or damaging

Protective:
- anti-inflammatory, e.g. TGFβ
- normal removal of unhealthy cells (i.e. homeostasis)

Damaging:
- pro-inflammatory, e.g. IL-1, TNF-α
- response to pathogens etc (i.e. damage to neurons = ‘collateral damage’)

Aging induces a shift towards production of damaging reactive microglia, due to changes in microglial gene expression

39
Q

How can the normal function of neuroinflammation be altered

A

External triggers such as AB, environmental toxins and pathogens can activate microglia which can cause neuronal death

40
Q

How can neuroinflammation be a cause of Alzheimers and PD

A

Many Alzheimer’s risk factors cause raised levels of circulating inflammatory cytokines:

  • High BP, Cardiovascular disease, Diabetes, Smoking
  • In principal, effects can cross the blood-brain barrier
  • Enough to cause AD? Not known

But an interesting story emerging in PD…

41
Q

Explain how gut inflammation cause PD

A
  • Lewy body pathology in gut often precedes pathology in brain
  • Evidence that gut inflammation is sufficient to cause gut Lewy bodies
  • Spread to brain via vagus nerve?
  • Role for microbiota?
42
Q

What are the other effects of ageing

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/β-catenin is decreased in adult brain
  • Deregulated Wnts in developmental and geriatric neuro conditions?!

Molecular Basis of Disease - SGUL (Sem 4) (29 decks)

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