Protein Misfolding and Aggregation as a Therapeutic Target for Polyglutamine Diseases

Abstract

The polyglutamine (polyQ) diseases, such as Huntington’s disease and several types of spinocerebellar ataxias, are a group of inherited neurodegenerative diseases that are caused by an abnormal expansion of the polyQ tract in disease-causative proteins. Proteins with an abnormally expanded polyQ stretch undergo a conformational transition to β-sheet rich structure, which assemble into insoluble aggregates with β-sheet rich amyloid fibrillar structures and accumulate as inclusion bodies in neurons, eventually leading to neurodegeneration. Since misfolding and aggregation of the expanded polyQ proteins are the most upstream event in the most common pathogenic cascade of the polyQ diseases, they are proposed to be one of the most ideal targets for development of disease-modifying therapies for polyQ diseases. In this review, we summarize the current understanding of the molecular pathogenic mechanisms of the polyQ diseases, and introduce therapeutic approaches targeting misfolding and aggregation of the expanded polyQ proteins, which are not only effective on a wide spectrum of polyQ diseases, but also broadly correct the functional abnormalities of multiple downstream cellular processes affected in the aggregation process of polyQ proteins. We hope that in the near future, effective therapies are developed, to bring hope to many patients suffering from currently intractable polyQ diseases.

Nanoscopic Insights of Amphiphilic Peptide against the Oligomer Assembly Process to Treat Huntington's Disease

“…[27] QBP1, a well-known synthetic peptide that has been identified through phage display screening, showed strong ability to prevent the misfolding and aggregation of the expanded polyQ protein in the cell and Drosophila model. [28] However, administration of this peptide drug showed limited therapeutic effect in R6/2 mice due to low drug delivery efficiency in targeting the brain. [29] Previous study has identified the application of the cell-penetrating peptide, for example, the arginine-rich sequence showed strong penetrating ability in the brain of Aβ transgenic mice [30] or adult zebrafish with low cytotoxic effect upon administration.…”

On the wrong DNA track: Molecular mechanisms of repeat-mediated genome instability

“…Accumulation of poly(Q) runs is believed to cause neurodegeneration (reviewed in Ref. 112). First discovered in 1997 for CAG repeats in HD (113), poly(Q) accumulation was used to explain symptoms of SCAs and other diseases caused by expansions of translated CAG repeats.…”

Autophagy in Neurodegenerative Diseases: A Hunter for Aggregates

“…HD is an autosomal-dominant progressive neurodegenerative disease, exhibiting motor dysfunction, behavioral disturbances, and cognitive dysfunction. The abnormal expansion of a polyQ repeat in exon 1 produces mHtt proteins that form ubiquitin-positive aggregates with β-sheet rich structures, leading to cytotoxicity in the striatum and cortex [181,182]. The overexpression of mHtt induces progressive motor deficits accompanied by the accumulation of autophagosomes [183,184].…”