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Fractionation for Resolution of Soluble and Insoluble Huntingtin Species
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Proteostasis of Huntingtin in Health and Disease

Seda Koyuncu1, Azra Fatima2, Ricardo Gutierrez-Garcia3

  • 1Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph Stelzmann Strasse 26, 50931 Cologne, Germany. skoyunc2@uni-koeln.de.

International Journal of Molecular Sciences
|July 30, 2017
PubMed

Insights

Huntington's disease (HD) involves mutations in the Huntingtin (HTT) gene, leading to protein aggregation and neurodegeneration. Maintaining protein homeostasis (proteostasis) is key to delaying HD onset, especially with aging.

Area of Science:

  • Neuroscience
  • Genetics
  • Molecular Biology

Background:

  • Huntington's disease (HD) is a fatal neurodegenerative disorder.
  • It stems from mutations in the Huntingtin (HTT) gene, causing polyglutamine (polyQ) repeat expansion.
  • Mutant HTT protein aggregates, contributing to neuronal dysfunction and death.

Purpose of the Study:

  • To review the intricate relationship between protein homeostasis (proteostasis), aging, and Huntington's disease.
  • To explore how proteostasis mechanisms influence HTT protein aggregation and degradation.
  • To understand the impact of aging on proteostasis and its role in HD pathogenesis.

Main Methods:

  • Literature review of studies on Huntington's disease, protein homeostasis, and aging.
  • Analysis of molecular mechanisms regulating Huntingtin (HTT) protein aggregation and clearance.
  • Examination of the interplay between aging processes and neuronal proteostasis in HD.

Main Results:

  • Mutant HTT aggregation, including fibrils and oligomers, is a key factor in HD neurodegeneration.
  • Protein homeostasis (proteostasis) pathways, such as chaperone-mediated folding and proteolysis, regulate HTT.
  • Impaired proteostasis, particularly during aging, exacerbates HD pathology.
  • Mechanisms preserving proteostasis can delay the onset and progression of HD.

Conclusions:

  • Proteostasis is critically linked to Huntington's disease pathogenesis and progression.
  • Aging diminishes the capacity to maintain proteostasis, increasing HD risk and severity.
  • Therapeutic strategies aimed at enhancing proteostasis may offer a promising avenue for HD treatment.

Keywords:
Huntington’s diseaseagingautophagychaperonesneurodegenerationproteasomeproteostasis

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