Spinocerebellar Ataxias Flashcards
Is SCA inheritance dominant or recessive?
Dominant
How many CAG repeats are normal and how many are found in SCA?
Normally ~22
In SCA ≥32
Which brain area is primarily affected and how?
Cerebellum
Purkinje cell loss - cerebellar atrophy
What are the symptoms of SCA?
Intention tremor Dysarthria Slow eye movement Hand dexterity problems Balance and coordination problems
Are all SCAs caused by excessive CAG repeats?
No
What is anticipation and why does it occur?
Intergenerational CAG repeat expansion - more repeats added during DNA replication
Causes earlier onset and more severe symptoms
What is the effect of Purkinje cell inhibition?
Tonic firing pause - downstream targets disinhibited - movement
SCA2 is caused by expanded CAG repeats in which gene?
ATXN2
What is the effect of expressing a 172Q human ATXN2 transgene in mouse Purkinje cells?
PC loss and dendritic atrophy
Impaired motor coordination
PC firing frequency gradually slows
What is the effect of ATXN2 KO in mice?
No effect on phenotype
No effect on PC morphology
What is the effect of mGluR activation in cerebellar PCs?
Activates 2nd messenger cascade
Activates IP3 receptors on internal Ca2+ stores
Ca2+ release from stores
How do polyQ-expanded ATXN1 and ATXN3 affect PCs?
Bind to and potentiate IP3R function - increase Ca2+ release from internal stores
How might mutations in Ca/mGluR-related genes lead to excitotoxicity?
Ca2+ positive feedback on IP3Rs and mGluRs
Increase IP3R opening - further increase Ca2+
Potentiate mGluR signalling cascade
What might be a common SCA pathogenic mechanism?
Hyperactive cerebellar PC mGluR-IP3R cascade - exacerbated by positive feedback loop
What are the advantages of antisense oligonucleotides?
Highly selective
Degradation-resistant
Durable
Well-tolerated
How is SCA2 linked to ALS?
Excessive ATXN2 repeats increase ALS risk
Many SCA2 patients have ALS symptoms - weakness, fasciculations
How might ATXN2 increase ALS risk?
Facilitates stress granule formation (TDP-43 aggregates) in TDP-43 ALS mouse model
What could be a treatment for both ALS and SCA2?
ATXN2 ASO
