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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

Define “Neurodegenerative disease”

A

Any disease caused by neurodegeneration

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3
Q

Briefly describe neurodegenerative diseases

A
  • Affects both CNS and PNS
  • Begin at any stage of life
  • The most common ones are associated with ageing
  • Rarer types of neurodegenerative disease start in childhood or even birth
  • Earlier age of onset = Greater genetic contribution
  • Later age of onset = More likely a sporadic (or idiopathic) disease (unknown cause)
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4
Q

Give some examples of neurodegenerative diseases

A
  • Alzheimer’s disease: 65 years or older = CNS
  • Parkinson’s disease: 40 years = CNS
  • Huntingtons disease: 40 years = CNS
  • Multiple Sclerosis: 20-50 years = CNS
  • Motor neurone disease: 40-70 years = PNS
  • Spinal muscular atrophy: From birth = PNS
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5
Q

Are neurodegenerative diseases heterogenous or homogeneous?

A

Are highly heterogeneous

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6
Q

In which 2 ways can Neurodegenerative diseases be seen as heterogenous?

A
  • This can be due to:
  • Some disease names are really umbrella terms: Conditions with overlapping phenotypes but distinct causes
  • Some diseases are inherently pleiotropic: Symptoms can manifest differently in different people
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7
Q

List some common features that some diseases have

A
  • Many follow a similar pattern: There’s a standard way in which neurons are lost
    1). Molecular impairment somewhere in the cell
    2). Decreased transmission at synapse
    3). “Dying back” of neurites (Axons and/or dendrites)
    4). Cell death

Distance between axon terminal and nucleus = A neurons “Achilles heel”

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8
Q

What is the term given to the distance between an axon terminal and nucleus?

A
  • A neurons “Achilles heel”
  • The weak point in any neuron because things have to be transported such a long way
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9
Q

What else do neurodegenerative disease have in common?

A
  • Frequently involve:
  • Protein aggregation (proteinopathies)
  • Lysosomal dysfunction
  • Mitochondrial dysfunction
  • Associated inflammation via activation of glia
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10
Q

What is one limitation of a neurodegene disease?

A
  • They rarely manifest overt signs and symptoms until long after the neurodegeneration has begun
  • Early treatment is impossible without early diagnosis
  • 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 cause
  • Neurodegenerative disease remain incurable
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11
Q

Briefly describe Alzheimer’s disease

A
  • The most common Neurodegenerative disease
  • The most common cause of dementia
  • Onset is usually > 65 years old but 10% are early onset starting at 30
  • incidence rate: 10% of people aged 65+, 50% of people aged 85+
  • Alzheimer’s disease is not a normal part of ageing, it’s a disease
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12
Q

What is dementia?

A
  • A decline in memory and other cognitive functions that impair your quality of life
  • Impairments in dementia are distinct from “normal” cognitive lapses
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13
Q

Give some situational examples of Alzheimer’s disease

A
  • Getting lost in your own neighbourhood
  • Not recognising a family member
  • Strong & irrational changes in mood
  • Sudden changes in personality
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14
Q

How do we tell the difference between normal ageing and dementia?

A
  • Normal ageing involves a gradual decline in normal cognition, gradual changes in personality
  • Impairments in dementia are distinct from normal cognitive lapses
  • Alzheimer’s disease is also fast and sudden
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15
Q

Give a history of Alzheimer’s disease

A
  • First described by Alois Alzheimer’s, a German psychiatrist and neuroanatomist in 1906
  • Initial psychiatric and pathological observations in younger patients
  • Discovered “Presenile dementia”
  • Pathology then found to be widespread in older patients
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16
Q

What is meant by the term “hallmark”?

A
  • In general, in a piece of jewellery where you have the precious metal, they have stamps in it which tell you how much carrots the gold is and the office which recorded it
  • In short, it’s the evidence that tell you what something is
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17
Q

What are the pathological hallmarks of Alzheimer’s disease?

A
  • Brain shrinkage: Quite clear
  • Shrinkage of the hippocampus, Cerebral cortex and enlarged ventricles
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18
Q

What are some other pathological hallmarks of Alzheimer’s disease?

A
  • At the cellular level:
  • Proteinopathies: The aggregation of proteins
  • Has 2 types
  • Amyloid plaques: Round bodies which sit outside the cell
  • Neurofibrillary tangles: Sit within the cell
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19
Q

Briefly describe the amyloid plaques

A
  • Sit outside the cell
  • Extracellular protein aggregates
  • Enriched in Abeta peptides
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20
Q

Briefly describe the Neurofibrillary tangles

A
  • Sit inside the cell
  • Also called paired helical filaments
  • Intracellular protein aggregates
  • Enriched in Tau protein
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21
Q

What is the Abeta peptide?

A
  • It’s a cleavage from a transmembrane domaine called the amyloid beta precursor protein (APP) by proteases
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22
Q

What do these cleavages lead to?

A
  • First there is a cleavage by B secretase -> another cleavage by Y secretase
  • Which then accumulate and forms amyloid plaques outside the cell
23
Q

Describe the Amyloid hypothesis

A
  • Mutations to 3 proteins involved in AB peptide processing are known to cause rare early onset forms of Alzheimer’s
  • These proteins are known as
  • APP, PSEN1 AND PSEN2
  • Both Presenilin-1 and Presenilin-2 are components of Y secretase
    Since early 1990’s “Amyloid hypothesis of AD” which states that Abeta and/or amyloid plaques are the causes of AD
24
Q

Describe Tau and Neurofibrillary tangles

A
  • Tau normally binds microtubules in axons (are normally intracellular proteins)
  • Hyperphosphorylated tau is displaced causing:
  • Tangles
  • Destabilised microtubules
25
Q

What is the importance of microtubules in neurites?

A
  • In all post mitosis cells, microtubules have 3 main roles:
  • Structure/Shape of the cell
  • Positioning of organelles
  • Motorways for transporting vesicular cargo
26
Q

Describe the Tau hypothesis

A
  • In typical late onset Alzheimer’s disease (not genetic forms of AD)
  • Seen before amyloid plaques
  • Well correlated with cell death and progression
  • Suggests Tau is upstream Abeta = Tau hypothesis
27
Q

So is the Tau hypothesis or the amyloid hypothesis correct?

A
  • Still really controversial
  • Probably more evidence for the amyloid but Therapies based on inhibiting Abeta aggregation so far haven’t worked
  • Tangles and plaques may be red herringsAre they pathogenic or by standers? Or even protective? Oligometric forms of Abeta are more likely to be pathogenic
  • Could both be downstream of other factors
28
Q

What are some other risk factors of Alzheimer’s disease?

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
29
Q

Describe Parkinson’s disease

A
  • The second most common Neurodegenerative disease
  • Onset 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
30
Q

Give a brief history of Parkinson’s disease

A
  • First reported in 1817 by James Parkinson, an east London physician
  • Described it a “Shaking palsy”
  • Identical symptoms described by a Hungarian physician, Ferenc Papai Pariz in 1690
  • However, the similar observations stretch back to ancient Egypt
31
Q

What are the symptoms of Parkinson’s disease?

A
  • A movement disorder, with 4 ‘cardinal’ features
  • Resting Tremor
  • Bradykinesia (Slow movement)
  • Rigidity (Stiff like posture)
  • Postural instability (Falling over)
32
Q

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

A
  • > 90% of patients display additional non motor symptoms including:
  • Depression & Anxiety
  • Loss of smell
  • Sleep disorders
  • Constipation
  • Dementia (less common)
  • Other psychiatric complications (less common)
33
Q

What are the pathological hallmarks of Parkinson’s disease?

A
  • Loss of dopaminergic neurons of the substantia nigra
  • The substantia nigra is a part of the basal ganglia in the midbrain (Dark substance)
  • The dark substance is due to the expression of neuromelanin
34
Q

What is the other pathological hallmarks of Parkinson’s disease?

A
  • Proteinopathy
  • Called Lewy bodies
  • Intracellular protein aggregates
  • Enriched in ã-synuclein protein
  • Normal role of ã-synuclein is poorly understood (Involved in neurotransmitter release
  • Lewy bodies not pathogenic, but increase ã-synuclein is
35
Q

Describe the genetic causes of Parkinson’s disease

A
  • 10% of cases have a clear genetic cause
  • 3 rough categories
    1. Early/Juvenile onset recessive mitochondrial conditions
    1. Late/later onset usually autosomal dominant PD
    1. Mutations that cause PD plus conditions
36
Q

Describe the 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 2 proteins central to activating mitophagy - PINK1 and Parkin - Cause of early onset PD
  • Mutations in at least 3 other genes linked to mitochondrial stress response also linked to EO PD
  • Limitation is distinct from late onset sporadic PD (A whole different disease?)
37
Q

Describe the later onset genetic PD

A
  • Some genetic causes found from kindred studies (like EO PD), but more limited including:
  • SCNA (a synuclein) gene amplification (Confirms that a synuclein is pathogenic)
  • LRRK2 gain of function
  • VPS35 gain of function
  • GBA loss of function
38
Q

How is GBA linked significantly to a-synuclein?

A
  • GBA encodes GCase (B-glucocerebrosidase), a lysosomal enzyme
  • a-synuclein is degraded in the lysosome
  • They are connected via..
39
Q

What happens between GCase and lysosomes in an ordinary person?

A
  • The GCase is trafficked into the lysosome
  • The lysosome is then satisfied and can act as the final part for autophagy
  • Where it can degrade a-synuclein so you don’t get Lewy bodies
40
Q

What happens in an individual that has a GBA mutation?

A
  • These individuals have less activity of GCase so there will be less active GCase in the lysosome
  • This causes the lysosome to become impaired
  • Leads to a corresponding reduction in its ability to serve as the last step in autophagy
  • a-synuclein is insufficiently degraded and accumulates
41
Q

What if you don’t have a GBA mutation but still have an increase in a-synuclein?

A
  • The excess a-synuclein inhibits the translocation of GCase into the lysosome
  • You then end up with an impaired lysosome
  • This lysosome will no longer be able to act efficiently in autophagy such that you get even more of a synuclein
  • This could be also known as a pathogenic feed forward loop, up a-synuclein-> down GCase -> down Lysosomal function -> a-synuclein
42
Q

How can Parkinson’s disease be linked to lysosomes?

A
  • Other PD genes play roles in processes involving lysosomes
  • Consistently autophagy is dysregulated in PD brain
  • Problems in autophagy will also lead to mitochondrial dysfunction (decrease mitophagy)
  • Endocytic pathways are a big focus in PD research
43
Q

Describe the GWAS results of Sporadic 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
44
Q

What does MAPT encode?

A

Tau

45
Q

What was found from the GWAS results of sporadic PD?

A
  • The linkage of MAPT to PD was a big surprise
  • Neurofibrillary tangles can be found in PD brains (even in same cells as Lewy bodies) but not to a greater extent
  • However: More NFTs in brains of LRRK2 PD
  • Microtubules disruption long implicated in PD
46
Q

What are other risk factors for PD?

A
  • Gender (more common in men)
  • Red hair (2x risk)
  • Head injury
  • Not smoking, not consuming caffeine
  • Herbicides, pesticides, insecticides
  • Exposure to metals
  • General anaesthesia
47
Q

What is meant by neuroinflammation?

A
  • The activation of the immune system within the nervous system
  • In the brain, this principally means activation of microfilm (astrocytes also involved)
48
Q

How does neuroinflammation work in neurodegenerarion?

A
  • Imagine the neurone is damaged with a neurotic insult (Injury or toxins) which causes a dying/damaged neurone
  • This releases factors which activates microglia
  • The microglia then becomes reactive microglia which will then secretes various neurotrophic factors such as IL-1B, TNF-a, Prostaglandins
  • This in turn triggers more cell damage and cell death
49
Q

Why is neuroinflammation important in neurodegeneration?

A

Produces another positive feed cycle

50
Q

How can ageing be linked to microglia?

A
  • Reactive microglia can be protective of neurons or damaging
  • Protective: Inflammatory or normal removal of unhealthy cells
  • Damaging: Pro-inflammatory, Response to pathogens
  • Ageing induces a shift towards production of damaging reactive microglia, due to changes in microglia plans gene expression (Neuroinflammaging)
51
Q

What evidence do we have of neuroinflammation as a cause?

A
  • Many Alzheimer’s risks causes 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 unknown
52
Q

What is the theory of Parkinson’s disease starting in the gut?

A
  • Lewy bodies 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
  • May have a role for microbiota
53
Q

What are the other effects of ageing?

A
  • Shortening of the telomeres in adult stem cells, can’t replace dying neurons
  • Increased reactive oxygen species
  • Other changes in gene expression: Altered Wnt signalling
  • Wnts are neuroprotective and neuromodulatory
  • Wnt/B-catenin is decreased in adult brain
  • Deregulated wnts in developmental and geriatric neuro conditions

Molecular Basis Of Disease (30 decks)

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