Potential therapeutic targets in polyglutamine-mediated diseases

Abstract

Polyglutamine diseases are a group of inherited neurodegenerative disorders that are caused by an abnormal expansion of a trinucleotide CAG repeat, which encodes a polyglutamine tract in the protein-coding region of the respective disease genes. To date, nine polyglutamine diseases are known, including Huntington’s disease, spinal and bulbar muscular atrophy, dentatorubral-pallidoluysian atrophy and six forms of spinocerebellar ataxia. These diseases share a salient molecular pathophysiology including the aggregation of the mutant protein followed by the disruption of cellular functions such as transcriptional regulation and axonal transport. The intraneuronal accumulation of mutant protein and resulting cellular dysfunction are the essential targets for the development of disease-modifying therapies, some of which have shown beneficial effects in animal models. In this review, the current status of and perspectives on therapy development for polyglutamine diseases will be discussed.

Keywords::

• autophagy
• biomarker
• disease-modifying therapy
• Huntington’s disease
• molecular chaperone
• polyglutamine
• spinal and bulbar muscular atrophy
• spinocerebellar ataxia
• translational research
• ubiquitin–proteasome

Financial & competing interests disclosure

This work was supported by KAKENHI from MEXT/JSPS, Japan (grant numbers 22110005, 26293206, 26670440, and 26670439); grants from Health Labor Sciences Research Grants, MHLW, Japan; CREST, JST; and a grant from the Daiichi Sankyo Foundation of Life Science. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Polyglutamine diseases are a group of inherited neurodegenerative disorders that are caused by an abnormal expansion of a trinucleotide CAG repeat.

• Intraneuronal accumulation of a polyglutamine-expanded protein is the pivotal molecular event that instigates neurodegeneration.

• Suppression of abnormal protein accumulation is a fundamental therapeutic strategy for polyglutamine diseases, but the effects of such therapies have not been clearly shown in clinical trials.

• Elucidation of downstream events, such as transcriptional dysregulation and mitochondrial dysfunction, provides molecular targets of disease-modifying therapy.

• Pathological and functional decline precedes the onset of clinical symptoms, suggesting the need for presymptomatic/early initiation of interventions.

• Development of biomarkers is indispensable for the evaluation of disease-modifying therapy at the prodromal stage of polyglutamine diseases.

Notes