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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.
Insights
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.
Abstract:
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a polyglutamine expansion mutation in the huntingtin protein. Expansions above 40 polyglutamine repeats are invariably fatal, following a symptomatic period characterised by choreiform movements, behavioural abnormalities, and cognitive decline. While mutant huntingtin (mHtt) is widely expressed from early life, most patients with HD present in mid-adulthood, highlighting the role of ageing in disease pathogenesis. mHtt undergoes proteolytic cleavage, misfolding, accumulation, and aggregation into inclusion bodies. The emerging model of HD pathogenesis proposes that the chronic production of misfolded mHtt overwhelms the chaperone machinery, diverting other misfolded clients to the proteasome and the autophagy pathways, ultimately leading to a global collapse of the proteostasis network. Multiple converging hypotheses also implicate ageing and its impact in the dysfunction of organelles as additional contributing factors to the collapse of proteostasis in HD. In particular, mitochondrial function is required to sustain the activity of ATP-dependent chaperones and proteolytic machinery. Recent studies elucidating mitochondria-endoplasmic reticulum interactions and uncovering a dedicated proteostasis machinery in mitochondria, suggest that mitochondria play a more active role in the maintenance of cellular proteostasis than previously thought. The enhancement of cytosolic proteostasis pathways shows promise for HD treatment, protecting cells from the detrimental effects of mHtt accumulation. In this review, we consider how mHtt and its post translational modifications interfere with protein quality control pathways, and how the pharmacological and genetic modulation of components of the proteostasis network impact disease phenotypes in cellular and in vivo HD models.