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.
Highlights
The polyglutamine 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
A study using knock-out mice demonstrated that heterozygous disruption of Hdh gene, a mouse homologue of human huntingtin gene, did not show apparent disease phenotypes, while homozygous disruption resulted in embryonic lethality, indicating that huntingtin has essential roles in the embryonic development, and loss of huntingtin does not mimic Huntington’s disease (HD) neuropathology [15]
These facts collectively indicate that the abnormal expansion of the polyQ repeat in disease-causative proteins has a pivotal role in the pathogenic mechanism of the polyQ diseases: recent studies have suggested that repeat RNA transcripts produced from sense/antisense sequences of the polyQ-disease genes, as well as proteins that are unconventionally translated from their transcripts via repeat-associated non-ATG (RAN) translation, contribute to the pathogenesis of polyQ diseases [29,30,31,32]
Summary
The polyglutamine (polyQ) diseases are a group of inherited neurodegenerative diseases characterized by a genetic mutation of cytosine-adenine-guanine (CAG) triplet repeat expansion in the coding regions of the disease-causative genes [1,2,3]. The CAG codon encodes the amino acid glutamine (one-letter code, Q), and its expansion in the disease-causative genes, results in the production of mutated proteins with an abnormally expanded polyQ tract. In 1991, Fischbeck and coworkers first reported the disease-associated expansion of CAG repeat in exon 1 of the androgen receptor gene in patients of spinal and bulbar muscular atrophy (SBMA) [4]. Similar genetic mutations of the CAG repeat expansion in the coding regions of genes other than androgen receptor gene have been found in other inherited neurodegenerative disorders [5,6,7]. Brain Sci. 2017, 7, 128; doi:10.3390/brainsci7100128 www.mdpi.com/journal/brainsci
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