期刊
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
卷 531, 期 1, 页码 51-55出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2020.01.054
关键词
G-quadruplexes; Neurological diseases; ATR-X syndrome; Porphyrins; 5-aminolevulinic acid
资金
- Japan Agency for Medical Research and Development (AMED)
- MEXT/JSPS [19H05221, 19K2380100]
- Takeda Science Foundation
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Tokyo Biochemical Research Foundation
- Grants-in-Aid for Scientific Research [19H05221] Funding Source: KAKEN
Genomic regions with guanine (G)-rich sequences make non-Watson-Crick base pairs, which result in the formation of unique nucleic acid structures called G-quadruplexes (G4s) in cells. Studies have suggested that abnormal G4s are involved in neurological diseases. For example, the formation of G4s caused by expansion of G-rich sequences is implicated in C9orf72-mediated amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD), and fragile X-related tremor/ataxia syndrome (FXTAS). In addition, the disruption and/or mutation of G4 binding proteins (G4BPs), such as heterogeneous nuclear ribonucleoproteins (hnRNPs) and DNA/RNA helicases, is related to neurological diseases. For instance, mutations in a G4BP called ATRX lead to a neurodevelopmental disorder, ATR-X syndrome, which is associated with intellectual disability. We found that porphyrins are potential candidate drugs for treating ATR-X syndrome through their G4 binding ability. Importantly, intracellular porphyrins are produced from 5-aminolevulinic acid (5-ALA) in vivo. Oral administration of 5-ALA improved cognitive dysfunction in an ATR-X syndrome model mouse, and language ability in an ATR-X syndrome patient. In this review, we suggest a novel therapeutic strategy targeting G4s using porphyrins in neurological diseases. (C) 2020 Elsevier Inc. All rights reserved.
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