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BIOL0027 > Ageing and Inherited Neurodegenerative Disorders > Flashcards

Ageing and Inherited Neurodegenerative Disorders Flashcards

1
Q

Why can inherited forms of dementia also be age-associated?

A

Inherited forms have early onset than sporadic forms - but still later onset than most genetic disorders
Disease-causing genes expressed from birth - no onset until later

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2
Q

Give an example of an age-associated inherited form of dementia

A

HD

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3
Q

What is the inheritance pattern of HD?

A

Autosomal dominant

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4
Q

What are the symptoms of HD?

A

Chorea - uncontrolled jerky movements
Bradykinesia - loss of voluntary movements
Dementia - depression, personality changehs, short-term memory impairment

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5
Q

How does the dementia in HD differ from that in AD?

A

In HD no long-term memory/language use deficits

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6
Q

What are the pathologies seen in HD?

A

White matter loss - ~15yrs before symptoms
Striatal degeneration
Protein aggregates in neurons

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7
Q

In which region of HTT does the CAG repeat expansion occur in HD?

A

Exon 1

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8
Q

What is the effect of having 6-35 CAG repeats in HTT?

A

No symptoms

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9
Q

What is the effect of having 36-39 CAG repeats in HTT?

A

Incomplete penetrance - HD in some - increased HD risk

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10
Q

What is the effect of having 40+ CAG repeats in HTT?

A

HD

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11
Q

What is the effect of more CAG repeats?

A

Earlier onset

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12
Q

What is the main trait of mHTT?

A

Unstable and sticky - abnormal interactions with other molecules

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13
Q

What is the main mechanism of HD?

A

Toxic gain-of-function

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14
Q

What is the effect of HTT mis-splicing in HD?

A

Forms mHTT fragments - aggregation prone

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15
Q

What is the effect of mHTT oligomers?

A

Disrupt neuronal function - via multiple pathways

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16
Q

Name the 3 ways in which mHTT fragments cause neuronal toxicity?

A

Transcriptional regulation
Mitochondrial dysfunction
Impaired protein quality control

17
Q

How do mHTT fragments affect transcriptional regulation?

A

Alter transcription factors

Alter gene packaging

18
Q

How do mHTT fragments cause mitochondrial dysfunction?

A

Increase permeability

Decrease ATP production

19
Q

How do mHTT fragments impair protein quality control?

A

Decrease protein folding/degradation

Feed-forward toxicity

20
Q

What is the main point supporting inherited neurodegenerative diseases as accelerated ageing?

A

Same mHTT-induced neuronal changes implicated in ageing

21
Q

What are the 2 models for the association of HD with age?

A

Progressive mHTT accumulation with age

Age-specific decline of pathways protecting against mHTT

22
Q

What are the possible treatment approaches?

A

Replace lost striatal MSNs
Promote mHTT clearance
Prevent mHTT synthesis

23
Q

How could lost striatal MSNs be replaced?

A

Neuronal stem cell transplants

24
Q

What are the steps of neuronal stem cell transplants?

A

Convert human embryonic stem cells (hESCs) to neuronal stem cells (NSCs)
Inject NSCs into striatum

25
Q

What is the effect of injecting NSCs into the striatum of HD model mice?

A

Transplanted NSCs integrate into striatum - differentiate into MSNs - express BDNF - promote health of surrounding neurons
Fewer mHTT aggregates in NSCs
Small improvement in rotarod performance (motor coordination)

26
Q

What are the potential problems with neuronal stem cell transplants?

A

Transplanted NSCs forming tumours
Rejection of transplanted NSCs
Unknown if new NSCs will degenerate later anyway

27
Q

What is the effect of HSP90 inhibitors and autophagy activators in Drosophila and mouse HD models?

A

Increase protein quality control pathway activity
Increased mHTT clearance - fewer aggregates
Small improvement in motor and cognitive function

28
Q

What is a potential problem with small molecules used to increase PQC pathway activity?

A

Many have long-term toxicity

29
Q

How could mHTT be silenced?

A

Antisense oligonucleotides (ASOs)

30
Q

What do HD ASOs do?

A

Cause HTT pre-mRNA degradation - decrease HTT and mHTT proteins

31
Q

What is the effect of mHTT ASOs in HD model mice?

A

Decreased mHTT aggregates
Prevented neuronal loss
Improved motor deficits - but not to WT level

32
Q

What are the effects of mHTT ASOs in humans?

A

Safe and efficacious

Unknown if long-term motor improvements

33
Q

Why are biomarkers important for HD treatment?

A

Enable early diagnosis - known which individuals to intervene in to prevent symptom presentation

BIOL0027 (20 decks)

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