Huntington's Disease Flashcards
Explain some common features of polyglutamate diseases.
All inherited - no sporadic cases.
Degree of anticipation - gets worse/onset gets earlier as is is passed through generations
CAG repeat size negatively correlates to age of onset.
Juvenile form - longer repeat extensions.
CAG repeat expansion encodes polyQ repeat.
Pretins affected in different diseases have no relation execeppt for polyQ tract.
Gain of function.
Symptoms of adult huntingtons?
midlife onset (appox 40)
movement disorder - chorea/dystonia
personality change -apathy, irritability, schizophrenia.
Cognitive decline - problems with info processing
Weight loss - due to muscle atrophy.
Symptoms of juvenile HD?
Onset before 20
Tremors, rigidity, bradykinesia and seizures.
Explain the different length of CAG repeats and the implication of this.
35 or less CAG = unaffected
36 - 39 CAG = increased likelihood of developing HD
more than 40 - causes disease within normal lifespan,
more than 70 - juvenile HD.
37Q tolerated - not 38…
35 CAG, CAA, CAG = 37 G = tolerated.
Does CAG repeat size help predict age of onset?
It may help predict the age of disease onset but this is unreliable and not the only indicator.
Explain the inheritance of HD…
CAG repeats increase in size when inherted from a male…large variation in sperm…large ranging CAG repeat sizes.
Longer CAG repeats associated with earlier onset.
Most juvenile HD cases inherit the mutation from their father.
Describe the huntingtin protein.
Expressed in all tissues throughout development.
Multi-functional scaffold protein.
Mutation imparts a gain of function.
Knock out mice - lethal.
Explain the Rb mouse model of HD.
beginning of gene and 150Q repeats. Mouse shows symptoms of a progressive neurological disorder 4 weeks - selective cell death 6 weeks - motor impariment 10 weeks: huntingtin aggregation.
Explain in vitro models of HD.
polyQ length dependant. concentration dependant. Time dependant. Correlates with pathogenic CAG repeat threshold. Dependant on Huntingtin protein content.
Small oligomers are thought to be most toxic.
What does the ubiqutin proteasome system do?
degrades protein.
What is the critical concentration of pathogenic substrate dependant on?
terminal differentiation
huntingtin expression level
glutamate length.
Explain the cellular dysfunction as a aresult of the Htt mutant polyQ.
Transcriptional dysregulation, mitochondrial impaiment, synaptic transmission, excitotoxicty, cell death —-> disease!
What is the molecular pathogensis of HD?
Proteolysis of Huntingtin Intracellular aggregation Transcriptional dysregulation. Impairment of folding and degradation networks. Mitochondrial impairment. Impairment of axonal transport Impairment of synaptic function.
What are the current theraputic possibilites?
Currently - symptomatic therapy.
1) movement disorder - neuroleptics
2) cognitive impairment
3) psychiatric symptoms - antidepressants, SSRIs
4) Disease progression
What are the future options for HD treatment?
1) Slow disease progression - drug combinations
2) Halt and reverse symptoms - interupt and reverse neuronal dysfunction
3) Postpone age of onset - predict those at risk and detection of early markers.
