Peptide-Based Therapeutic Approaches for Treatment of the Polyglutamine Diseases
Toshihide Takeuchi, H. Akiko Popiel, Shiroh Futaki, Keiji Wada and Yoshitaka Nagai
Affiliation: Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan.
Keywords: Neurodegeneration, peptide, polyglutamine diseases, protein aggregation, therapy.
The polyglutamine (polyQ) diseases including Huntington’s disease and spinocerebellar ataxias are a group of
inherited neurodegenerative diseases that are caused by an abnormal expansion of the polyQ stretch in disease-causative
proteins. The expanded polyQ stretches are intrinsically unstable and are prone to form insoluble aggregates and inclusion
bodies. Recent studies have revealed that the expanded polyQ proteins gain cytotoxicity during the aggregation process,
which may possibly cause detrimental effects on a wide range of essential cellular functions leading to eventual neuronal
degeneration. Based on the pathogenic mechanism of the polyQ diseases, several therapeutic approaches have been proposed
to date. Among them, here we focus on peptide-based approaches that target either aggregate formation of the
polyQ proteins or abnormal cellular processes induced by the expanded polyQ proteins. Although both approaches are effective
in suppressing cytotoxicity of the abnormal polyQ proteins and the disease phenotypes of animal models, the former
approach is more attractive since it targets the most upstream change occurring in the polyQ diseases, and is therefore
expected to be effective against various downstream functional abnormalities in a broad range of polyQ diseases. One of
the major current problems that must be overcome for development of peptide-based therapies of the polyQ diseases is the
issue of brain delivery, which is also discussed in this article. We hope that in the near future effective therapies are developed,
and bring hope to many patients suffering from the currently untreatable polyQ diseases.
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