TY - JOUR
T1 - Pharmacological prospects of G-quadruplexes for neurological diseases using porphyrins
AU - Asamitsu, Sefan
AU - Yabuki, Yasushi
AU - Ikenoshita, Susumu
AU - Wada, Takahito
AU - Shioda, Norifumi
N1 - Funding Information:
This work was supported by the Practical Research Project for Rare/Intractable Diseases from the Japan Agency for Medical Research and Development (AMED) (N.S.), Grant-in Scientific Research on Innovation Areas "Constructive understanding of multi-scale dynamism of neuropsychiatric disorders” (grant number 19H05221 ) from MEXT/JSPS to N.S., and Grant-in-Aid for Young Scientists (Start-up) (grant number 19K2380100 ) from MEXT/JSPS to S.A. This research was also partially supported by the Takeda Science Foundation (N.S.), Mochida Memorial Foundation for Medical and Pharmaceutical Research (N.S.), and the Tokyo Biochemical Research Foundation (N.S.).
PY - 2020/10/8
Y1 - 2020/10/8
N2 - 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.
AB - 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.
KW - 5- aminolevulinic acid
KW - ATR-X syndrome
KW - G-quadruplexes
KW - Neurological diseases
KW - Porphyrins
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U2 - 10.1016/j.bbrc.2020.01.054
DO - 10.1016/j.bbrc.2020.01.054
M3 - Article
AN - SCOPUS:85078152486
VL - 531
SP - 51
EP - 55
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
SN - 0006-291X
IS - 1
ER -