Ageing and Inherited Neurodegenerative Disorders Flashcards
Why can inherited forms of dementia also be age-associated?
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
Give an example of an age-associated inherited form of dementia
HD
What is the inheritance pattern of HD?
Autosomal dominant
What are the symptoms of HD?
Chorea - uncontrolled jerky movements
Bradykinesia - loss of voluntary movements
Dementia - depression, personality changehs, short-term memory impairment
How does the dementia in HD differ from that in AD?
In HD no long-term memory/language use deficits
What are the pathologies seen in HD?
White matter loss - ~15yrs before symptoms
Striatal degeneration
Protein aggregates in neurons
In which region of HTT does the CAG repeat expansion occur in HD?
Exon 1
What is the effect of having 6-35 CAG repeats in HTT?
No symptoms
What is the effect of having 36-39 CAG repeats in HTT?
Incomplete penetrance - HD in some - increased HD risk
What is the effect of having 40+ CAG repeats in HTT?
HD
What is the effect of more CAG repeats?
Earlier onset
What is the main trait of mHTT?
Unstable and sticky - abnormal interactions with other molecules
What is the main mechanism of HD?
Toxic gain-of-function
What is the effect of HTT mis-splicing in HD?
Forms mHTT fragments - aggregation prone
What is the effect of mHTT oligomers?
Disrupt neuronal function - via multiple pathways
Name the 3 ways in which mHTT fragments cause neuronal toxicity?
Transcriptional regulation
Mitochondrial dysfunction
Impaired protein quality control
How do mHTT fragments affect transcriptional regulation?
Alter transcription factors
Alter gene packaging
How do mHTT fragments cause mitochondrial dysfunction?
Increase permeability
Decrease ATP production
How do mHTT fragments impair protein quality control?
Decrease protein folding/degradation
Feed-forward toxicity
What is the main point supporting inherited neurodegenerative diseases as accelerated ageing?
Same mHTT-induced neuronal changes implicated in ageing
What are the 2 models for the association of HD with age?
Progressive mHTT accumulation with age
Age-specific decline of pathways protecting against mHTT
What are the possible treatment approaches?
Replace lost striatal MSNs
Promote mHTT clearance
Prevent mHTT synthesis
How could lost striatal MSNs be replaced?
Neuronal stem cell transplants
What are the steps of neuronal stem cell transplants?
Convert human embryonic stem cells (hESCs) to neuronal stem cells (NSCs)
Inject NSCs into striatum
What is the effect of injecting NSCs into the striatum of HD model mice?
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)
What are the potential problems with neuronal stem cell transplants?
Transplanted NSCs forming tumours
Rejection of transplanted NSCs
Unknown if new NSCs will degenerate later anyway
What is the effect of HSP90 inhibitors and autophagy activators in Drosophila and mouse HD models?
Increase protein quality control pathway activity
Increased mHTT clearance - fewer aggregates
Small improvement in motor and cognitive function
What is a potential problem with small molecules used to increase PQC pathway activity?
Many have long-term toxicity
How could mHTT be silenced?
Antisense oligonucleotides (ASOs)
What do HD ASOs do?
Cause HTT pre-mRNA degradation - decrease HTT and mHTT proteins
What is the effect of mHTT ASOs in HD model mice?
Decreased mHTT aggregates
Prevented neuronal loss
Improved motor deficits - but not to WT level
What are the effects of mHTT ASOs in humans?
Safe and efficacious
Unknown if long-term motor improvements
Why are biomarkers important for HD treatment?
Enable early diagnosis - known which individuals to intervene in to prevent symptom presentation
