2020.05.27
Arginine is a disease modifier for polyQ disease models that stabilizes polyQ protein conformation
(Brain. 2020 May 21;awaa115. doi: 10.1093/brain/awaa115. Online ahead of print.)
Minakawa EN1, Popiel HA1,2, Tada M3, Takahashi T3, Yamane H1, Saitoh Y1, Takahashi Y4, Ozawa D5, Takeda A5, Takeuchi T1,5, Okamoto Y1,2, Yamamoto K1, Suzuki M1,5, Fujita H1, Ito C2, Yagihara H1, Saito Y6, Watase K7, Adachi H8, Katsuno M8, Mochizuki H9, Shiraki K10, Sobue G8, Toda T2, Wada K1, Onodera O3, Nagai Y1,2,5,9.
1Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry.
2Division of Clinical Genetics, Osaka University Graduate School of Medicine.
3Department of Neurology, Brain Research Institute, Niigata University.
4Olympus Corporation.
5Department of Neurotherapeutics, Osaka University Graduate School of Medicine.
6Department of Pathology and Laboratory Medicine, National Center Hospital, National Center of Neurology and Psychiatry.
7Center for Brain Integration Research, Tokyo Medical and Dental University.
8Department of Neurology, Nagoya University Graduate School of Medicine.
9Department of Neurology, Osaka University Graduate School of Medicine.
10Faculty of Pure and Applied Sciences, University of Tsukuba.
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.
*Reproduced by permission of Oxford University Press on behalf of the Guarantors of Brain.
