Elizabeth Talbot by

Huntingtons Disease

bs23e2t2 — 2023-11-20 18:21:50 UTC

what is it?

bs23e2t2 — 2023-11-20 18:22:05 UTC

It is a hereditary neurodegenerative disorder which attacks regions of the brain that control voluntary movements. people who suffer from HD experience uncontrollable movements and suffer cognitive problems associated with thinking, personality and behaviour (NHS, 2021)

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Molecular mechanisms:

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Molecular mechanism involved in the disorder involve protein misfolding whereby the mutant huntington protein adopts an abnormal conformation and aggregates. Aggregation interferes with neurons and causes toxicity (Denecke, J 2023). HD caused by a mutation in the HTT gene. the mutation increases the length of the CAG segment within the N-terminal domain of the Huntington protein. Alpha-synuclein is misfolded and adopts an abnormal structure.

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cellular processes:

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protein degradation: occurs in HD as the excess of unfolded proteins causes aggregation creating an abnormal protein structure (Denecke, J 2023). Autophogy occurs whereby the protein fuses with the lysosome to begin degradation (Emilia, M 2020).

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Gene Expression: HD is caused by a mutation in the gene huntingtin which causes DNA base pairs to repeat more times than usual. people with HD have significantly more CAG sequences present.

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cell signalling: HD affects neurons in the striatum (area in brain involved in motor control) and thus disrupts the balance of neurotransmitters, including dopamine. HD also damages and kills nerve cells in response to this neurotransmitter imbalance. As a result, glutamate receptors have increased sensitivity resulting in neuronal damage.

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figure 4: how nerve impulses should normally work.

Mitochondrial Dysfunction: HD affects energy production in cells which can contribute to nerve cell depletion. the mutant huntingtin gene can also interfere with calcium (causing changes with release of excitatory amino acids --> excitatory)within mitochondria (Ichiyama, R 2023). causing imbalance in charge as well as altering how the mitochondria functions causing the development of abnormal mitochondria structures. (Denecke, J 2023)

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figure 2: mitochondria effected by HD

How HD affects normal function of human systems?

bs23e2t2 — 2023-11-20 20:23:09 UTC

Huntington’s disease damage’s normal function of nerve cells in the brain. Basal ganglia in the brain of people with HD are smaller than normal due to how nerve cells of the striatum die first.

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Direct pathway- The internal globus pallidus receives less neurotransmitters and releases more neurotransmitter than usual ‘downstream’ from the IGP, making it more inhibited. As a result, motor cortex under-stimulated causing slower than usual general movement.

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figure 1: degenerative process of the striatum in Huntington's disease.

(Matz, O and Spocter, M 2022)

Indirect pathway- overstimulation of motor cortex. External globulus pallidus release more neurotransmitter to the subthalamic nuclei. Causing it to be more inhibited than usual. Thalamus releases more neurotransmitter to the motor cortex which results in over stimulation.

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Motor: chorea- involves uncontrollable movements. Dysarthria and Dysphagia- difficulty speaking and swallowing. motor impairment- overtime individuals with HD have poor coordination, balance and posture (mayo clinic, 2022)

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Cognitive Impairment: dementia- as the disease progresses and worsens, it can lead to dementia. this occurs as nerve cells are increasingly damaged and processing speed decreases. however, it is argued whether the memory loss caused by HD is dementia as the memory loss is different. (mayo clinic, 2022)

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Personality: HD can lead to changes in personality as individuals may become irritable and withdrawn. also linked to depression and anxiety as mood changes occur due to changes within the brain.

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references:

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Schulte J 2011. PubMed, biological function of the Huntington protein and its relevance to huntington’s disease pathology, Curr Trends neurol, volume 5, pp 65-78 Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3237673/#:~:text=It%20is%20caused%20by%20expansion,most%20severe%20in%20the%20striatum.

NHS (2021), Huntington’s disease. Available at : https://www.nhs.uk/conditions/huntingtons-disease/

Labbadia, J Morimoto, R, ‘Huntington’s disease: underlying molecular mecahmism and emerging concepts’, trends in biochemical sciences, vol 38.8, pp378-385. (online) Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955166/

Matz, O Spocter, M 2022, ‘the Effect of Huntington’s Disease on the Basal Nuclei: A review’, Cureus, volume 14. (online) available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9132741/#:~:text=As%20Huntington's%20disease%20progresses%2C%20there,funnelled%20into%20the%20direct%20pathway.

Denecke, J 2023, ‘protein folding, membrane insertion and proteolytic processing’ FOBS2235T Basis of Life, University of Leeds.

Ichiyama, R 2023, ‘spinal cord injury’, BMSC1100T, structure and function (anatomy and physiology) of human body systems, University of Leeds.

Harrison, M 2023, 'nitorgen excretion and urea cycle', FOBS2235T, Basis of lIFE, university of Leeds.

protein misfolding causes Huntington's disease as it disrupts cellular processes and interferes with functions of organelles within the brain. cellular stress may occur meaning homeostasis does not occur within protein. patients who have suffered many years of HD may experience apoptosis of neurons.

bs23e2t2 — 2023-11-21 12:55:05 UTC

bs23e2t2 — 2023-11-21 13:06:29 UTC

figure 3: direct pathway affected by too much neurotransmitter release.

glutamate also involved in nitrogen excretion within the kidneys --> transamination + deamination and disposal of ammonia within the liver. carbomyl phopshate synthesis occurs when glutamate levels are high --> control step in urea synthesis.(Harrison 2023).

bs23e2t2 — 2023-11-22 15:08:52 UTC