Ageing and Inherited Neurodegenerative Disorders

Question 1

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

Answer 1

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

Question 2

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

Answer 2

HD

Question 3

What is the inheritance pattern of HD?

Answer 3

Autosomal dominant

Question 4

What are the symptoms of HD?

Answer 4

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

Question 5

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

Answer 5

In HD no long-term memory/language use deficits

Question 6

What are the pathologies seen in HD?

Answer 6

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

Question 7

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

Answer 7

Exon 1

Question 8

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

Answer 8

No symptoms

Question 9

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

Answer 9

Incomplete penetrance - HD in some - increased HD risk

Question 10

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

Answer 10

HD

Question 11

What is the effect of more CAG repeats?

Answer 11

Earlier onset

Question 12

What is the main trait of mHTT?

Answer 12

Unstable and sticky - abnormal interactions with other molecules

Question 13

What is the main mechanism of HD?

Answer 13

Toxic gain-of-function

Question 14

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

Answer 14

Forms mHTT fragments - aggregation prone

Question 15

What is the effect of mHTT oligomers?

Answer 15

Disrupt neuronal function - via multiple pathways

Question 16

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

Answer 16

Transcriptional regulation
Mitochondrial dysfunction
Impaired protein quality control

Question 17

How do mHTT fragments affect transcriptional regulation?

Answer 17

Alter transcription factors

Alter gene packaging

Question 18

How do mHTT fragments cause mitochondrial dysfunction?

Answer 18

Increase permeability

Decrease ATP production

Question 19

How do mHTT fragments impair protein quality control?

Answer 19

Decrease protein folding/degradation

Feed-forward toxicity

Question 20

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

Answer 20

Same mHTT-induced neuronal changes implicated in ageing

Question 21

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

Answer 21

Progressive mHTT accumulation with age

Age-specific decline of pathways protecting against mHTT

Question 22

What are the possible treatment approaches?

Answer 22

Replace lost striatal MSNs
Promote mHTT clearance
Prevent mHTT synthesis

Question 23

How could lost striatal MSNs be replaced?

Answer 23

Neuronal stem cell transplants

Question 24

What are the steps of neuronal stem cell transplants?

Answer 24

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

Question 25

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

Answer 25

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)

Question 26

What are the potential problems with neuronal stem cell transplants?

Answer 26

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

Question 27

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

Answer 27

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

Question 28

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

Answer 28

Many have long-term toxicity

Question 29

How could mHTT be silenced?

Answer 29

Antisense oligonucleotides (ASOs)

Question 30

What do HD ASOs do?

Answer 30

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

Question 31

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

Answer 31

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

Question 32

What are the effects of mHTT ASOs in humans?

Answer 32

Safe and efficacious | Unknown if long-term motor improvements

Question 33

Why are biomarkers important for HD treatment?

Answer 33

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