Lecture 4: Huntington's and Motor Neuron Disease Flashcards
What are some of the clinical signs and symptoms of HD?
Involuntary bowing, twisting, grimacing movements often with facial and vocal tics
slow or abnormal eye movements
difficulty with speech and swallowing
sometimes memory problems/dementia
psychiatric symptoms (hallucinations and delusions)
What is usually the cause of death in HD?
patients often die 15-20 years after signs first appear from a secondary cause (such as heart failure)
Describe the pathology behind HD?
severe loss of neurons in the sub-cortical regions - largely in the caudate-putamen of the basal ganglia = brain weight reduced by about 30%
enlargement of lateral ventricles (CSF in lateral ventricles expands to fill the space and compensate due to loss of neurons)
Cells in cerebral cortex may also be affected (variable between people)
Gliosis (inflammation associated with neuronal death)
What are the alterations to neurotransmitter systems in HD (motor circuit)?
Glutamate excitotoxicity (primarily in the caudate putamen that drives the death of cholinergic and GABAergic neurons here)
How does dopamine neurotransmission differ in the early and later stages of HD?
biphasic changes in dopamine neurotransmission:
- early stages = increased dopamine release = contributes to hyperactivation of thalamus = increased stimulation of motor cortex that increases movement
- later stages = lose dopaminergic input
How does the biphasic changes in dopamine neurotransmission in HD affect response to treatments?
giving L-dopa (used to compensate for loss of dopamine) in early stages will aggravate symptoms but dopamine antagonists will alleviate symptoms
as the disease progresses, you might see a reversal of this
How is HD inherited?
autosomal dominant inheritance
What is the age of onset?
usually 40-50 (although children constitute about 10% of the cases)
What phenomenon is displayed by HD?
genetic anticipation (worsening of the disease phenotype over generations)
True or false: inheritance from mother is likely to result in more severe disease?
False: inheritance from father is likely to result in more severe disease
How does the number of CAG repeats relate to age of onset?
Individuals with higher number of CAG repeats have an earlier onset of disease
What is the name of the gene and protein involved in HD?
gene: IT-15
protein: huntingtin (Htt)
Where is huntingtin found?
throughout brain and in the testes
What is the function of huntingtin?
unknown but may act as a transcription factor or contribute to protein trafficking or endocytosis/membrane cycling in neurons
What evidence shows huntingtin is essential for normal embryonic development?
Huntingtin KO mice is embryonic lethal
True or false: HD is a repeat expansion disorder?
True
What is the nucleotide repeat implicated in HD?
trinucleotide CAG repeat within exon 1 of coding region of huntingtin near N-terminus
What three things does the length of the CAG repeat determine in HD?
Whether an individual will develop HD (E.g. 36 repeats and above = affected, 40 repeats and above results in adult-juvenile onset)
degree of penetrance
age of onset
disease severity
Describe the Huntingtin protein (Htt)
cytosolic protein with molecular weight around 350 KDa
- N-terminal PolyQ region begins at amino acid 18
- PolyQ region followed by PolyP (polyproline) region which is thought to keep the Htt in solution
- multiple HEAT domains that are thought to play a role in vesicle trafficking
- Nuclear export signal
- nuclear localisation signal
How is the wildtype huntingtin protein post-translationally modified to form non-toxic fragments?
don’t have the long polyQ repeat = cleavage of n-terminal fragment by caspases
- N-terminal fragment interacts with C-terminal fragment
How is the mutant huntingtin protein post-translationally modified to form toxic fragments?
- long polyQ repeat domain = alternate cleavage of Htt to generate a larger N-terminal fragment that is not able to interact with the C-terminus (mis-folded) resulting in an aggregate property.
How do expanded polyQ Htt proteins aggregate?
form detergent-insoluble protein aggregates with characteristics of amyloid fibrils
- aggregate into oligomers, intermediates then fibrils but still debate over which species is most toxic
How does the distribution of Htt change in HD?
changes from cytoplasm to peri/nuclear (forms nuclear inclusions)
Which neurons predominantly contain the Htt nuclear inclusions?
Neurons of the caudate-putamen and cortex
What experimental evidence has suggested that Htt amyloid fibrils may be the more toxic species?
> 30 CAG repeats results in fibril formation with longer repeats aggregating faster and at lower concentrations
Htt inclusions form before the onset of neurological symptoms and neurodegeneration
so questions whether these aggregates are the cause of the disease
What experimental evidence has suggested that Htt amyloid fibrils may be the least toxic species?
cultured human neurons and developed a robotic microscope that could track the fate of each cell in the dish
- expressed the GFP tagged Htt protein to see where the Htt distributed
- found that in some cells, they developed red Htt inclusions but the neuron was healthier than the neurons surrounding it
suggested that the neurons with intranuclear inclusions were actually protected from death and suggesting that perhaps the fibrillar species was actually the least toxic
What are the potential targets of disease-modifying treatments for HD?
- depletion or stabilisation of dopamine, serotonin and other monoamines involved in pathogenesis and biphasic responses
- antioxidants to reduce free-radicals
- anti-sense oligonucleotide treatment to silence the expression of the IT-15 gene (risky bc don’t understand the physiological role of the protein so maybe just target repeat domains in exon 1)
- stem cell therapy
What are some of the current treatments for HD?
Symptomatic treatments:
- physical therapy to treat motor issues
- rebalance the neurotransmitter systems (GABA, glutamate, acetylcholine, dopamine)
What is motor neuron disease also called?
Amyotrophic lateral sclerosis
What is MND?
progressive, fatal disease that attacks nerve cells controlling voluntary muscles
What are some of the clinical features and symptoms of MND?
muscle atrophy, weakness and
muscle twitch that signify disease of the lower motor neurons
glial scar in the lateral columns of the spinal cord at autopsy following degeneration of the corticospinal tracts
loss of brain’s ability to initiate and control voluntary movement
difficulty speaking, swallowing and eventually breathing
What is the typical cause of death in patients with MND?
respiratory failure
True or false: dementia is often seen in individuals with MND nearer the end of disease?
False:
cognitive function is often spared but about 10% of cases develop a type of dementia
What is the difference between upper and lower motor neurons?
Upper motor neurons originate in the motor cortex in the cerebral cortex and travel down to, and synapse in, the brain stem and spinal cord
lower motor neurons begin in the spinal cord and brain stem and innervate the muscles throughout the body
True or false: men are more likely to develop MND than women?
True
What is the typical age of MND onset?
late middle age, peak 60-70 years
What is the mean duration of survival for individuals diagnosed with MND?
3 to 5 years
True or false: most cases of MND are familial?
False: most are sporadic (around 90%)
What is one of the first genes identified that, when mutated, increases risk of developing familial MND?
mutations in Cu/Zn superoxide mismutase (SOD1)
what mutations in which gene accounts for around 40% of familial MND cases?
expanded hexanucleotide repeat (GGGGCC) in C9ORF72
Other than SOD1 and C9ORF72, which other mutations have been identified associated with familial MND?
mutations in DNA/RNA-binding proteins:
TAR DNA binding protein (TDP-43) and Fused in sarcoma (FUS
What are three environmental risk factors of MND?
- consumption of beta-methylaminoalanine (BMAA)
- exposure to pesticides
- exposure to viruses
Give three occupations that are risk factors for MND?
professional athletes
served in the military
farmers
Give three lifestyle risk factors of developing MND?
- head trauma
- smoking
- diet/obesity
What evidence suggests that glutamate excitotoxicity may have a pathological role in MND?
elevated levels of glutamate have been found in CSF and serum of those with MND
treatment with glutamate antagonist Riluzole delays disease progression
What factors may contribute to the development MND?
glutamate excitotoxicity
failure of UPS
mitochondrial dysfunction
oxidative damage
Describe the pathology of MND
degeneration and loss of motor neurons with astrocyte gliosis
intraneuronal inclusions
- main component in the pathology is TDP-43 but may also see ubiquitin deposits, Bunina bodies, SOD1 or FUS aggregates, poly-(Gly-Ala), poly-(Gly-Pro) and poly-(Gly-Arg) dipeptide repeat proteins in C9orf72
What is the most common protein aggregate observed in intraneuronal inclusions in MND?
TDP-43
What are the two approved treatments for MND?
Riluzole and Edaravone
What is Riluzole and what does it do for treatment of MND?
a glutamate antagonist so targets excessive glutamate in excitotoxicity that delays death or time to tracheostomy
What is Edaravone and what does it do for treatment of MND?
an antioxidant and free-radical scavenger that delays motor deterioration
What are potential targets in the pipeline for MND treatment?
- reduce oxidative stress and mitochondrial dysfunction
- reduce excitotoxicity
- reduce neuroinflammation (astrogliosis)
- apoptosis and stem cell therapies - replace the motor neuron
- nucleocytoplasmic transport
- DNA damage and RNA splicing/metabolism
polymorphisms in which gene encoding an anti-inflammatory protein is a risk factor for AD, MND and PD?
TREM2
