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Targeting the proteostasis network in Huntington's disease
Tânia R Soares1, Sara D Reis2, Brígida R Pinho2
1REQUIMTE/LAQV, Department of Drug Sciences, Pharmacology Lab, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal; Department of Cell and Developmental Biology, University College London, London, WC1E 6BT, UK.
Ageing Research Reviews
|December 4, 2018
Summary
Huntington's disease involves mutant huntingtin protein aggregation, overwhelming cellular protein quality control. Targeting proteostasis pathways offers a promising therapeutic strategy for this neurodegenerative disorder.
Area of Science:
- Neurodegenerative Disorders
- Molecular Biology
- Genetics
Background:
- Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder.
- Caused by polyglutamine expansion in the huntingtin protein (mHtt).
- Disease onset is influenced by aging, despite early mHtt expression.
Purpose of the Study:
- To review how mHtt interferes with protein quality control pathways.
- To explore the role of aging and organelle dysfunction in HD pathogenesis.
- To examine the impact of modulating proteostasis network components on HD models.
Main Methods:
- Review of current literature on HD pathogenesis and proteostasis.
- Analysis of mHtt interactions with cellular protein quality control mechanisms.
- Evaluation of studies on proteostasis modulation in cellular and in vivo HD models.
Main Results:
- Chronic mHtt production overwhelms chaperone machinery, leading to proteostasis collapse.
- Mitochondrial dysfunction and mitochondria-ER interactions are implicated in HD.
- Enhancing cytosolic proteostasis pathways shows therapeutic potential.
Conclusions:
- mHtt accumulation disrupts cellular proteostasis, contributing to HD pathogenesis.
- Ageing exacerbates HD by impacting organelle function and proteostasis.
- Targeting the proteostasis network presents a viable therapeutic avenue for Huntington's disease.