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Molecular Pathogenesis in Huntington’s Disease, Essays (university) of Neurobiology

The molecular pathogenesis of Huntington's disease, a neurodegenerative disorder that causes progressive breakdown of nerve cells in the brain. It explains the role of transcription factors and the increase in the number of copies of glutamine encoding CAG repeats in the HTT gene that causes the disease. The document also provides information on the symptoms, prevalence, and treatment of Huntington's disease.

Typology: Essays (university)

2021/2022

Available from 06/29/2023

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Neurobiology - PBL1 Assignment
Molecular Pathogenesis in Huntington’s Disease
Authors: S. N. Illarioshkin, S. A. Klyushnikov, V. A. Vigont, Yu. A. Seliverstov, and E. V.
Kaznacheyeva
Date of publication: May 21st, 2018
UPDATED: May 31st, 2018
Summary
Huntington’s disease, also known as HD, is a neurodegenerative disorder and an inherited
disease that causes progressive breakdown of nerve cells in the brain that causes a decrease in the
size of the basal ganglia and cerebral cortex. Given that neurons control our ability to move, feel,
and regulate activities in our bodies, a degeneration to nerve cell has an impact on all of these
functions which causes; movement disorders since neurons produce action potentials in order to
allow muscle contract as well as cognitive disorders since neurons are responsible with the
ability to -among other functions- produce speech which occurs in Broca’s area, more about that
in the next section. Due to the degeneration of neurons, the size of the Basal ganglia and cerebral
cortex are decreased. The worldwide prevalence of the disease is 0.38 pers 100,000 per year
(Pringsheim et al., 2012) . Huntigton’s is caused by a defect in a single gene and a person only
needs one copy of that defective gene to become a carrier which is why Huntigton’s is classified
as an autosomal dominant disorder in the central nervous system. The symptoms do not begin
from birth, they usually appear at the age of 30 50 years of age. The disease causes death 10
20 years after a person starts to show symptoms. There is no treatment to treat Huntigton’s given
that it is at the genetic level and very little is understood about gene therapy, but there are
medications that can be used to offset some of the symptoms that patients have.
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Neurobiology - PBL1 Assignment Molecular Pathogenesis in Huntington’s Disease Authors: S. N. Illarioshkin, S. A. Klyushnikov, V. A. Vigont, Yu. A. Seliverstov, and E. V. Kaznacheyeva Date of publication: May 21st, 2018 UPDATED: May 31st, 2018 Summary Huntington’s disease, also known as HD, is a neurodegenerative disorder and an inherited disease that causes progressive breakdown of nerve cells in the brain that causes a decrease in the size of the basal ganglia and cerebral cortex. Given that neurons control our ability to move, feel, and regulate activities in our bodies, a degeneration to nerve cell has an impact on all of these functions which causes; movement disorders since neurons produce action potentials in order to allow muscle contract as well as cognitive disorders since neurons are responsible with the ability to -among other functions- produce speech which occurs in Broca’s area, more about that in the next section. Due to the degeneration of neurons, the size of the Basal ganglia and cerebral cortex are decreased. The worldwide prevalence of the disease is 0.38 pers 100,000 per year (Pringsheim et al., 2012). Huntigton’s is caused by a defect in a single gene and a person only needs one copy of that defective gene to become a carrier which is why Huntigton’s is classified as an autosomal dominant disorder in the central nervous system. The symptoms do not begin from birth, they usually appear at the age of 30 – 50 years of age. The disease causes death 10 – 20 years after a person starts to show symptoms. There is no treatment to treat Huntigton’s given that it is at the genetic level and very little is understood about gene therapy, but there are medications that can be used to offset some of the symptoms that patients have.

Pathogenesis : Huntington’s is caused by an increase in the number of copies of glutamine encoding CAG repeats in a gene called the HTT gene. This abnormal expansion of polyglutamine repeats within the gene happens in exon 1 of the HTT gene 4p16.3. The mutation leads to elongation of the polyQ tract which is a protein that consists of sequence of several glutamine units. The polyQ tract of Huntington acts as a flexible domain that is essential for appropriate intramolecular proximity, as well as substrate specificity. This is altered by the extended CAG repeats which causes genetic instability both in gametogenesis (formation of gametes) and spermatogenesis (formation of sperm) and in somatic tissue. The larger the size of the expanded HTT allele the higher the polymorphism of Huntington’s clinical features. The others in this paper determined that the number of CAG repeats directly correlates with a rate of Huntington’s progression. Role of Transcription Factors: Transcription factors are proteins that bind to the promoter and help RNA Polymerase bind to the promoter. Given that glutamine tracts are often found in transcription factors and are responsible for protein-protein interaction at the activation of transcriptional complexes, then a hypothesis was established that may provide more insight to polyglutamine diseases (which includes Huntington’s). The hypothesis states that mutant polyglutamine-containing peptide molecules, being accumulated in the nucleus of neurons, aberrantly interact with different transcription factors (which are proteins that interact with other resides in order to allow transcription to occur) hence violating transcription factors is correlated to violating their functions in allowing transcription.

  1. Ament, Seth A et al. “Transcriptional regulatory networks underlying gene expression changes in Huntington's disease.” Molecular systems biology vol. 14,3 e7435. 26 Mar. 2018, doi:10.15252/msb.
  2. Illarioshkin, S.N., Klyushnikov, S.A., Vigont, V.A., Seliverstov, Yu.A., and Kaznacheyeva, E.V. (2018). Molecular Pathogenesis in Huntington’s Disease. Biochemistry Moscow 83 , 1030–1039.
  3. Pringsheim, T., Wiltshire, K., Day, L., Dykeman, J., Steeves, T., and Jette, N. (2012). The incidence and prevalence of Huntington’s disease: a systematic review and meta-analysis. Mov Disord 27 , 1083–1091.
  4. Roos RA. Huntington's disease: a clinical review. Orphanet J Rare Dis. 2010;5:40. Published 2010 Dec 20. doi:10.1186/1750-1172-5-