Arginine is a disease modifier for polyQ disease models that stabilizes polyQ protein conformation.

Abstract

The polyglutamine (polyQ) diseases are a group of inherited neurodegenerative diseases that include Huntington's disease, various spinocerebellar ataxias, spinal and bulbar muscular atrophy, and dentatorubral pallidoluysian atrophy. They are caused by the abnormal expansion of a CAG repeat coding for the polyQ stretch in the causative gene of each disease. The expanded polyQ stretches trigger abnormal β-sheet conformational transition and oligomerization followed by aggregation of the polyQ proteins in the affected neurons, leading to neuronal toxicity and neurodegeneration. Disease-modifying therapies that attenuate both symptoms and molecular pathogenesis of polyQ diseases remain an unmet clinical need. Here we identified arginine, a chemical chaperone that facilitates proper protein folding, as a novel compound that targets the upstream processes of polyQ protein aggregation by stabilizing the polyQ protein conformation. We first screened representative chemical chaperones using an in vitro polyQ aggregation assay, and identified arginine as a potent polyQ aggregation inhibitor. Our in vitro and cellular assays revealed that arginine exerts its anti-aggregation property by inhibiting the toxic β-sheet conformational transition and oligomerization of polyQ proteins before the formation of insoluble aggregates. Arginine exhibited therapeutic effects on neurological symptoms and protein aggregation pathology in Caenorhabditis elegans, Drosophila, and two different mouse models of polyQ diseases. Arginine was also effective in a polyQ mouse model when administered after symptom onset. As arginine has been safely used for urea cycle defects and for mitochondrial myopathy, encephalopathy, lactic acid and stroke syndrome patients, and efficiently crosses the blood-brain barrier, a drug-repositioning approach for arginine would enable prompt clinical application as a promising disease-modifier drug for the polyQ diseases.

• Authors: Eiko N Minakawa, Helena Akiko Popiel, Masayoshi Tada, Toshiaki Takahashi, Hiroshi Yamane, Yuji Saitoh, Yasuo Takahashi, Daisaku Ozawa, Akiko Takeda, Toshihide Takeuchi, Yuma Okamoto, Kazuhiro Yamamoto, Mari Suzuki, Hiromi Fujita, Chiyomi Ito, Hiroko Yagihara, Yuko Saito, Kei Watase, Hiroaki Adachi, Masahisa Katsuno, Hideki Mochizuki, Kentaro Shiraki, Gen Sobue, Tatsushi Toda, Keiji Wada, Osamu Onodera, Yoshitaka Nagai
• Journal: Brain : a journal of neurology (Brain) Vol. 143 Issue 6 Pg. 1811-1825 (06 01 2020) ISSN: 1460-2156 [Electronic] England
• PMID: 32436573 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: [email protected].

Chemical References

• Molecular Chaperones
• Peptides
• polyglutamine
• Arginine

Topics

• Animals
• Arginine (metabolism, pharmacology)
• Caenorhabditis elegans (metabolism)
• Disease Models, Animal
• Drosophila (metabolism)
• Female
• Heredodegenerative Disorders, Nervous System (genetics)
• Huntington Disease (genetics)
• Male
• Mice
• Mice, Inbred Strains
• Molecular Chaperones (genetics)
• Peptides (genetics, metabolism)
• Protein Aggregation, Pathological
• Protein Conformation (drug effects)
• Protein Folding (drug effects)
• Spinocerebellar Ataxias (genetics)