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- Title
Arginine is a disease modifier for polyQ disease models that stabilizes polyQ protein conformation.
- Authors
Minakawa, Eiko N; Popiel, Helena Akiko; Tada, Masayoshi; Takahashi, Toshiaki; Yamane, Hiroshi; Saitoh, Yuji; Takahashi, Yasuo; Ozawa, Daisaku; Takeda, Akiko; Takeuchi, Toshihide; Okamoto, Yuma; Yamamoto, Kazuhiro; Suzuki, Mari; Fujita, Hiromi; Ito, Chiyomi; Yagihara, Hiroko; Saito, Yuko; Watase, Kei; Adachi, Hiroaki; Katsuno, Masahisa
- 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.
- Subjects
SPINOCEREBELLAR ataxia; MELAS syndrome; PROTEIN conformation; ARGININE; SPINAL muscular atrophy; HUNTINGTON disease; PROTEIN folding; INSECT metabolism; ARGININE metabolism; BIOCHEMISTRY; BIOLOGICAL models; RESEARCH; NEMATODES; MOLECULAR chaperones; ANIMAL experimentation; RESEARCH methodology; GENETIC disorders; EVALUATION research; MEDICAL cooperation; PHENOMENOLOGY; COMPARATIVE studies; MOLECULAR structure; PEPTIDES; MICE; NEURODEGENERATION
- Publication
Brain: A Journal of Neurology, 2020, Vol 143, Issue 6, p1811
- ISSN
0006-8950
- Publication type
journal article
- DOI
10.1093/brain/awaa115