Huntington's Disease Flashcards
What is Huntington’s disease (HD)? Symptoms?
= also known as Huntington’s chorea or St Vitus’s dance
= involuntary bowing, twisting, grimacing movements
= often with muscular (facial) and vocal ‘tics’
= slow or abnormal eye movements
= difficulty with speech or swallowing
= hallucinations
What is the pathology of HD?
= brain weight reduced by 30%
= severe loss of neurons in caudate-putamen
= enlargement of lateral ventricles
= cells in cerebral cortex can be affected (variable gliosis)
What is the HD motor pathway?
Alterations in multiple transmitter systems
= glutamate excitotoxicity
= deficits in cholinergic and GABAergic neurons in CPU
= biphasic changes in dopamine neurotransmission
(increased in early stages BUT decreased in later stages)
(L-dopa aggravates symptoms of HD)
(dopamine antagonists alleviate symptoms)
= Direct pathway overacted in HD = uncontrolled movement
What is the inheritance pattern of HD?
= autosomal dominant disease
(does NOT arise from spontaneous mutations)
= increases in severity through generations
Prevalence = 5-10 / 100,000 (UK)
Males + females equally affected
Onset age = 40-50
(children make up approx. 10% of HD cases)
What is the Huntington gene?
= IT-15 (on chromosome 4)
= codes for HUNTINGTIN
(348 kDa protein found throughout brain and in testes)
= function is unknown
(could act as a transcription factor / contribute to protein trafficking / endocytosis / membrane cycling in neurons)
Why does HD vary in penetrance, age of onset and disease severity?
HD is a trinucleotide repeat or polyglutamine disease
= expansion of trinucleotide CAG within exon 1 of coding region of huntingtin (near N-terminus)
= can NOT predict the inheritance of repeat length
= length of glutamine expansion determines degree of penetrance, age of onset + disease severity
What is the structure of the Huntingtin protein (Htt)?
= 3144 a.a cytosolic protein
= approx. 350 kDa
= polyglutamine (polyQ) tract begins at amino acid 18
= followed by polyproline (polyP) (thought to help keep huntingtin in solution)
= interacts with many HIP proteins (huintingtin-interacting proteins)
How does Htt aggregate?
= htt fragments containing expanded polyQ form detergent-insoluble protein aggregates
(with characteristics of amyloid fibrils)
= aggregation of htt fragments go into oligomers, intermediates and fibrils
(debate over which form is most toxic species)
= (Scherzinger et al., 1999)
= looked at ability of N-terminal huntingtin fragments with 20-83 CAG repeats to form amyloid-like fibrils
= 20,27 repeats do NOT form fibrils
= 30 repeats DO form fibrils
(longer repeats aggregate faster and at lower concentrations)
= huntingtin inclusions form before neurological symptoms + neurodegeneration
= ? suggests aggregates are the toxic speices
EXTRA READING
= some suggest the soluble oligomers / small insoluble aggregates are more toxic than larger insoluble fibrils / inclusion bodies
= cus smaller aggregates can more easily enter cells and disrupt normal cellular functions (E.g. proteasome, autophagy activity, mitochondrial function, synaptic signalling)
What is the HD disease mechanism?
Glutamate expansions cause cell death
= ? toxic gain of function OR ? loss of function
In HD
= change in distribution of huntingtin from cytoplasm to peri/nuclear
= neurons in CPU and cortex contain aggregates of mutant hutingtin = nuclear inclusions
EXTRA READING (cause cell death)
= disrupt normal function
= interaction with glutamate receptors (e.g. NMDA receptor) - disrupts signalling
= increase in intracellular calcium levels
= activation of cascade of events resulting in cell death = EXCITOTOXICITY
Why may Nuclear Htt inclusions be protective?
Using robotic microscope to track hundreds of individual cultured neurons expressing mutant htt
= PolyQ-expanded htt was tagged with GFP to see protein distribution
= accumulation of inclusion bodies and neuronal survival tracked over time
= showed healthy neuron contained an inclusion body in the nucleus
(BUT none have formed in sickly neurons)
What are some treatments of HD?
= depletion or stabilisation of dopamine, serotonin and other monoamines
= antioxidants
= anti-sense oligonucleotide (ASO) treatment to silence the IT-15 gene
(short, synthetic pieces of DNA = bind to mRNA and alter protein production)
(reduce production of mutant Htt protein - slow disease progression)
= stem cell therapy
(transplant healthy stem cells to replace damaged or lost neurons)
EXTRA READING
= other drugs that target excitotoxicity, inflammation and mitochondrial dysfunction (symptomatic)
= immunotherapy
(antibodies to target and clear toxic proteins from the brain)
= gene silencing therapies
(e.g. RNA interference = reduce production of mutant Htt protein)
(pre-clinical and clinical trials)
