Huntingtons Disease Flashcards
What is huntingtons disease?
A neurodegenerative disorder which affects movement (chorea) cognition (learning and memory) and emotional state (depression and suicide). The disease onset is 35-44 and death is normally due to secondary issues such as pneumonia/lower RT infections.
What is the genetic basis of huntingtons disease?
It results from an autosomal dominant gene (IT15) found on the short arm of chromosome 4. The gene for HD contains a trinucleotide CAG repeat (coding for glutamate). This gene codes for huntingtin.
How does the number of CAG repeats dictate the severity of the disease, and how do the CAG repeats increase?
The more CAG repeats, the more severe the condition and the more severe the onset. 39 - develops HD Because the intermediate number of CAG repeats is unstable, the repeats can increase with each generation, especially through the fathers line. This is because during the formation of gametes, there can be replication slippage, which is more likely to occur in spermatogenesis
What is huntingtin, and how does a mutant form cause cell death?
Huntingtin is a large protein made with 2144 amino acids. The polyglutamine domain begins at the 18th residue. The protein is involved in intracellular transport and chromosomal segregation. In HD, the mutant protein causes cel death through gain of function associated with the polyglutamine region. It forms large aggregates with other proteins within the cytoplasm, nucleus and axon terminals. The aggregates are formed from insoluble fibres of the misfolded protein, which cannot be broken down by the ubiquitin-proteosome system. This is primarily seen in the striatum and cortex.
What are the theories of how mutant huntingtin aggregates lead to neuronal death?
- The large protein is cleaved and small toxic N terminal fragments of huntingtin move passively to the nucleus where they form nuclear inclusions and block normal transcription. 2. The mutant huntington aggregates also prevent transcription factors moving into the nucleus; stop endocytosis and stop vesicle trafficking. 3. The aggregates do not cause neuronal death. but are the neurones method of protecting itself by inactivating the toxic fragments As a result of one or more of these theories, the neurones degenerate by: Exocitotoxicity - overactivation of neurones Altered Ca2+ signalling - over activation of glutamate receptors Apoptosis - normal huntingtin blocks apoptosis triggers Defective energy metabolism - defect in mitochondria and neurotransmitter release Oxidative stress - production of toxic free radicals in the neuron
How does neuronal death in Huntingtons disease lead to loss of movement control?
Loss of striatal neurons is a hallmark of HD
In the control of movement there are two major pathways in which the cerebral cortex and striatum control movement. The direct, which facilitates movement; and the indirect, which inhibits movement.
In early stage HD, neurones between the striatum and the globus palidus external begin to die, increasing the amount of inhibtion the GPe exerts on the subthalamic nucleus, resulting in excessive movement (chrorea)
In late stage HD, neurones between the striatum and the GPe die completely and those between the striatum and the GPi are reduced. This increases the inhibitory effects of the thalamus, resulting in a loss of movement.
What are the future potential therapies for Huntington’s disease?
Prevention:
Targetting mutant genes via RNA interferene, where a virus is injectedm which expresses a gene for a short hairpin RNA against the mutant huntingtin protein. Results have shown to decrease mutant protein expresion and increase patient motor function in stride length tests
Cell replacement:
Transplantation of neuonres or stem cells, however these may not restore normal function; as they are dependant on cells survivng and becoming mature functional neurones, and reconecting the circuit.
