Special Issue "Polyglutamine (PolyQ) Disorders"

A special issue of Brain Sciences (ISSN 2076-3425).

Deadline for manuscript submissions: closed (30 April 2017).

Special Issue Editor

Dr. Edamakanti Chandrakanth Reddy
E-Mail Website
Guest Editor
Department of Neurology, Northwestern University Feinberg School of Medicine, 303 East Chicago Avenue, Ward 10-321, Chicago, IL 60611-4296, USA
Interests: molecular mechanism of neurodegenerations; therepeutic implicatoins; iPSCs-based disease modeling; antisense oligonucleotide (ASO) based therapy

Special Issue Information

Dear Colleagues,

The polyglutamine (PolyQ) expansion disease family encompasses at least nine heritable disorders, including Huntington disease (HD) and the spinocerebellar ataxias SCA1, SCA2, SCA3 (Machado-Joseph disease), SCA6, SCA7, SCA17, spinal bulbar muscular atrophy (SBMA), and dentatorubral-pallidoluysian atrophy. At the molecular level, diseases are results from the expansion of CAG repeat that codes for the glutamine tract. A pathological hallmark of disorders is progressive neurodegeneration with accumulation of mutant protein aggregates. It is still unknown if these aggregates are pathogenic or protective to the cells. It is widely believed that the gain of protein function is primary cause for pathological events.  From recent and intriguing findings, it is known that repeat associated non-ATG (RAN) translation and RNA gain of toxic functions (e.g., HD) also play a crucial role in determining pathology. In most PolyQ disorders, the severity of disease is inversely correlated with the length of the PolyQ repeat.

Even though mutant proteins express ubiquitously, the molecular mechanism behind the selective vulnerability of each disorder is unknown. Lack of knowledge regarding this phenomenon has hampered the study of disease pathogenesis, as well as the identification of biomarkers to monitor disease progression. Understanding the molecular dysfunctions which take place before disease onset is particularly relevant for therapeutic purposes, as a possible pharmacologic intervention targeting the pre-symptomatic stages of disease is more likely to prevent its later clinical manifestation.

Dr. Chandrakanth Edamakanti
Guest Editor

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Keywords

  • CAG repeatlenth disorders
  • Spinocerebellar Ataxias
  • Atrophy of cerebellum
  • Huntington’s disease
  • Movement disorders
  • Spinal and bulbar muscular atrophy

Published Papers (3 papers)

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Review

Open AccessReview
Protein Misfolding and Aggregation as a Therapeutic Target for Polyglutamine Diseases
Brain Sci. 2017, 7(10), 128; https://doi.org/10.3390/brainsci7100128 - 11 Oct 2017
Cited by 14
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Polyglutamine (PolyQ) Disorders)
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Open AccessReview
Cognitive Changes in the Spinocerebellar Ataxias Due to Expanded Polyglutamine Tracts: A Survey of the Literature
Brain Sci. 2017, 7(7), 83; https://doi.org/10.3390/brainsci7070083 - 14 Jul 2017
Cited by 6
Abstract
The dominantly-inherited ataxias characterised by expanded polyglutamine tracts—spinocere bellar ataxias (SCAs) 1, 2, 3, 6, 7, 17, dentatorubral pallidoluysian atrophy (DRPLA) and, in part, SCA 8—have all been shown to result in various degrees of cognitive impairment. We survey the literature on the [...] Read more.
The dominantly-inherited ataxias characterised by expanded polyglutamine tracts—spinocere bellar ataxias (SCAs) 1, 2, 3, 6, 7, 17, dentatorubral pallidoluysian atrophy (DRPLA) and, in part, SCA 8—have all been shown to result in various degrees of cognitive impairment. We survey the literature on the cognitive consequences of each disorder, attempting correlation with their published neuropathological, magnetic resonance imaging (MRI) and clinical features. We suggest several psychometric instruments for assessment of executive function, whose results are unlikely to be confounded by visual, articulatory or upper limb motor difficulties. Finally, and with acknowledgement of the inadequacies of the literature to date, we advance a tentative classification of these disorders into three groups, based on the reported severity of their cognitive impairments, and correlated with their neuropathological topography and MRI findings: group 1—SCAs 6 and 8—mild dysexecutive syndrome based on disruption of cerebello-cortical circuitry; group 2—SCAs 1, 2, 3, and 7—more extensive deficits based largely on disruption of striatocortical in addition to cerebello-cerebral circuitry; and group 3—SCA 17 and DRPLA—in which cognitive impairment severe enough to cause a dementia syndrome is a frequent feature. Full article
(This article belongs to the Special Issue Polyglutamine (PolyQ) Disorders)
Open AccessReview
Striatal Vulnerability in Huntington’s Disease: Neuroprotection Versus Neurotoxicity
Brain Sci. 2017, 7(6), 63; https://doi.org/10.3390/brainsci7060063 - 07 Jun 2017
Cited by 6
Abstract
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease caused by the expansion of a CAG trinucleotide repeat encoding an abnormally long polyglutamine tract (PolyQ) in the huntingtin (Htt) protein. In HD, striking neuropathological changes occur in the striatum, including loss of medium [...] Read more.
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease caused by the expansion of a CAG trinucleotide repeat encoding an abnormally long polyglutamine tract (PolyQ) in the huntingtin (Htt) protein. In HD, striking neuropathological changes occur in the striatum, including loss of medium spiny neurons and parvalbumin-expressing interneurons accompanied by neurodegeneration of the striosome and matrix compartments, leading to progressive impairment of reasoning, walking and speaking abilities. The precise cause of striatal pathology in HD is still unknown; however, accumulating clinical and experimental evidence suggests multiple plausible pathophysiological mechanisms underlying striatal neurodegeneration in HD. Here, we review and discuss the characteristic neurodegenerative patterns observed in the striatum of HD patients and consider the role of various huntingtin-related and striatum-enriched proteins in neurotoxicity and neuroprotection. Full article
(This article belongs to the Special Issue Polyglutamine (PolyQ) Disorders)
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