Modulation of Molecular Chaperones in Huntington’s Disease and Other Polyglutamine Disorders

Abstract

Polyglutamine expansion mutations in specific proteins underlie the pathogenesis of a group of progressive neurodegenerative disorders, including Huntington's disease, spinal and bulbar muscular atrophy, dentatorubral-pallidoluysian atrophy, and several spinocerebellar ataxias. The different mutant proteins share ubiquitous expression and abnormal proteostasis, with misfolding and aggregation, but nevertheless evoke distinct patterns of neurodegeneration. This highlights the relevance of the full protein context where the polyglutamine expansion occurs, and suggests different interactions with the cellular proteostasis machinery. Molecular chaperones are key elements of the proteostasis machinery and therapeutic targets for neurodegeneration. Here we provide a focused review on Hsp90, Hsp70, and their cochaperones, and how their genetic or pharmacological modulation affects the proteostasis and disease phenotypes in cellular and animal models of polyglutamine disorders. The emerging picture is that, in principle, Hsp70 modulation may be more amenable for long-term treatment by promoting a more selective clearance of mutant proteins than Hsp90 modulation, which may further decrease the necessary wild-type counterparts. It seems, nevertheless, unlikely that a single Hsp70 modulator will benefit all polyglutamine diseases. Indeed, available data, together with insights from effects on tau and alpha-synuclein in models of Alzheimer's and Parkinson's diseases, indicates that Hsp70 modulators may lead to different effects on the proteostasis of different mutant and wild-type client proteins. Future studies should include the further development of isoform selective inhibitors, namely to avoid off-target effects on Hsp in the mitochondria, and their characterization in distinct polyglutamine disease models to account for client protein-specific differences.

Proteomic interrogation of HSP90 and insights for medical research

“…As a chaperone, HSP90 plays an important role in proteostasis, and logically the role of HSP90 in such diseases has been the focus of several studies [54–57], though mostly not using proteomics techniques. For example, HSP90 interacts with both tau and the hyper-phosphorylated proteoform of tau, which plays a key role in Alzheimer’s disease (AD).…”

A role of cellular translation regulation associated with toxic Huntingtin protein

“…Cellular proteostasis is regulated through a careful orchestration of protein synthesis, it’s folding and degradation [33]. In HD models, while the involvement of protein folding pathways through chaperone networks and proteasomal degradation pathways are well studied [5, 18, 20, 22, 35, 41, 51], its connection to protein synthesis is not very well established. There are several indicators pointing towards such a plausible connection.…”

Mitochondrial Chaperones in the Brain: Safeguarding Brain Health and Metabolism?

“…Since a hallmark of neurodegenerative diseases is the loss of (mito)proteostasis leading to the accumulation of aggregated proteins in the brain and in neurons ( 165 ), it is not surprising that its origin may underlie in mitochondrial dysfunction triggered by the disruption of the mitochaperone network followed by increased ROS formation which ultimately leads to protein carbonylation and aggregation. Along this line, aggregates are seen in most of neurodegenerative diseases, this includes the accumulation of Aβ and hyperphosphorylated tau in AD ( 166 ), the accumulation of synuclein in PD ( 167 ) or of the mutant form of the huntingtin protein in HD ( 168 ). Hyperphosphorylated tau has been also observed in brains of insulin receptor deficient mice ( 169 ).…”