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31 Cards in this Set
- Front
- Back
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What is the genetic inheritance of HD?
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Autosomal dominant
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What determines age of onset?
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The increased number of repeats, the lower the age of onset
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What is the prevalence of HD in people of European background?
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1/10,000
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What degree of penetrance is HD?
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100%
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What groups is HD less prevalent in ?
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Asian and African populations
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What is the age of onset of HD?
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Usually 35-50 years but can range from 2-85 years.
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What is the life expectancy after HD onset?
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15-20 years
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What are some HD-related causes of death?
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Pneumonia, heart disease, falls, suicide, violence
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Where is the Htt gene expressed?
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Widespread expression in peripheral tissues and in the brain Htt is expressed in neurons and is essential for development
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What happens if you were to get 2 dominant copies of the allele (mutation)?
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It is lethal in utero
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What neurons seems to be the most vulnerable to levels of Htt?
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Striatal neurons
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Who is the woman studying HD in Venezuela community?
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Nancy Wexler
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What causes mutation in Htt gene?
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Expansion in the size of a CAG repeat tract in exon 1 causes HD (glutamine = Q)
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What is the normal levels of poly Q?
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<35
40-60 = adult onset HD >60 = juvenile onset HD |
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How does anticipation relate to HD? Does paternal or maternal have greatest effect?
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Age of onset tends to decrease in successive generations, and anticipation is more likely when inheritance from a paternal carrier is present
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What are some modifier genes involved in HD?
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GluR6 (kainate receptor) is associated with earlier onset
ApoE4 increases age of onset (protective effect) ApoE2/3 associated with earlier onset Variants of NMDA receptor influence disease severity |
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What environmental factors effect HD onset?
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w-3 (marine oil) are protective
w-6 (red meat) causes susceptibility intellectual stimulation slows disease progression |
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How many neurodegenerative diseases are there that are caused by an expanded polyQ tract?
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9
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What is true of polyQ diseases?
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They involve proteolytic cleavage liberating toxic fragments, they develop neuronal inclusions, they have protein folding defects, and neurodegeneration
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How does HD mutation effect proteases?
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Expanded polyQ enhances the rate of cleavage and ends up producing the toxic fragment, instead of being degraded like the wild type, it translocates to the nucleus where it becomes trapped and forms protein aggregates
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What is HD and all polyQ diseases associated with?
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Defects in protein folding and the ubiquitin-proteasome pathway
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When do nuclear inclusions appear?
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Before clinical symptoms
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What are the major cellular defects associated with HD?
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1) dysregulation of transcription caused by toxic nuclear aggregates
2) altered neurotransmitters and excitotoxicity 3) interference with wildtype Htt, changes in axonal transport and synaptic function 4) apoptosis 5) oxidative stress due to mitochondrial dysfunction and altered energy metabolism |
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What is one of the major targets of transcription in HD?
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CBP ( a histone actetyltransferase that opens up and permits) is a major target.
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Explain the altered neurotransmitters in HD?
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Loss of medium spiny neurons causes GABAergic deficiencies, thus increasing movement if GABA levels are down
Also, upregulation of NMDA receptors causes excitotoxicity associated with chronic exposure to excitatory AA such as glutamine and glutamate which activate the NMDA receptor |
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What are places along the corticostriatal pathway where excitotoxicity may play a role?
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1.) increased glutamate release from afferents
2.) reduced reuptake of glutamate by glia 3.) hypersensitivity on post-synaptic NMDA-Rec to glutamate 4.) altered intracellular Ca homeostasis 5.) mitochondrial dysfunction |
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In adult neurons, what is wildtype Htt involved in?
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Vesicle transport, ctyoskeletal transport, endocytosis, synaptic function, and stimulation of BDNF
The mutant form can interfere with wt function |
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When does apoptosis occur in HD?
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At the end stage of disease there is cell death
Activates pro-apoptotic caspases Inhibition of cleavage of mutant Htt into fragments reduces cell death |
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How does HD cause oxidative stress and mitochondrial dysfunction?
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Excitotoxicity releases huge amounts of intracellular Ca that results in mito dysfunction and release of cytochrome c leading to activation and cell death
Htt interacts with PGC-1alpha on mito membranes and may play a role in weight loss and mito dysfunction. PGC-1alpha is downregulated in HD |
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How is allele-specific siRNA a potential therapy for HD?
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They would target the Htt mRNA that has long polyQ repeats
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What is predictive genetic counseling?
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Purpose: accurate risk assessment
Usually done in person with no symptoms but who is at risk because of family history |
