Pubmed du 02/05/22
1. Katayama Y. [Deciphering pathogenesis of autism spectrum disorder with mice model]. Nihon yakurigaku zasshi Folia pharmacologica Japonica. 2022; 157(3): 187-90.
Autism spectrum disorder (ASD) is a developmental disorder characterized by communication disorders and behavioral limitations, and its high prevalence has attracted increasing social attention in recent years. However, the pathogenesis of ASD is still not fully understood because of its diversity and the suspected involvement of many causative genes and environmental factors. Therefore, analyses using animal models that can isolate and simplify the causes of ASD are thought to be helpful in understanding the disease. In this article, we will introduce the pathogenic mechanism of ASD revealed by the analysis using a mouse model reproducing the mutation of CHD8, which is a reliable candidate gene for the cause of ASD, and discuss the possibility of therapeutic targets predicted from this analysis.
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2. Lin CW, Septyaningtrias DE, Chao HW, Konda M, Atarashi K, Takeshita K, Tamada K, Nomura J, Sasagawa Y, Tanaka K, Nikaido I, Honda K, McHugh TJ, Takumi T. A common epigenetic mechanism across different cellular origins underlies systemic immune dysregulation in an idiopathic autism mouse model. Molecular psychiatry. 2022.
Immune dysregulation plays a key role in the pathogenesis of autism. Changes occurring at the systemic level, from brain inflammation to disturbed innate/adaptive immune in the periphery, are frequently observed in patients with autism; however, the intrinsic mechanisms behind them remain elusive. We hypothesize a common etiology may lie in progenitors of different types underlying widespread immune dysregulation. By single-cell RNA sequencing (sc-RNA seq), we trace the developmental origins of immune dysregulation in a mouse model of idiopathic autism. It is found that both in aorta-gonad-mesonephros (AGM) and yolk sac (YS) progenitors, the dysregulation of HDAC1-mediated epigenetic machinery alters definitive hematopoiesis during embryogenesis and downregulates the expression of the AP-1 complex for microglia development. Subsequently, these changes result in the dysregulation of the immune system, leading to gut dysbiosis and hyperactive microglia in the brain. We further confirm that dysregulated immune profiles are associated with specific microbiota composition, which may serve as a biomarker to identify autism of immune-dysregulated subtypes. Our findings elucidate a shared mechanism for the origin of immune dysregulation from the brain to the gut in autism and provide new insight to dissecting the heterogeneity of autism, as well as the therapeutic potential of targeting immune-dysregulated autism subtypes.
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3. Shioda N. [The cellular functions of G-quadruplex in neurological diseases]. Nihon yakurigaku zasshi Folia pharmacologica Japonica. 2022; 157(3): 182-6.
G-quadruplex (G4) is a unique nucleic acid structure that formed when a four-stranded structure is produced within a single-stranded guanine-rich sequence. Four guanine molecules form a square planar arrangement, termed G-quartet, which are stacked on top of each other to form the G4 structure in DNA (G4DNA) and in RNA (G4RNA). Recent studies have revealed that G4DNA and G4RNA are folded in cells, which suggested their biological and pharmacological significance in DNA replication, transcription, epigenetic modification, and RNA metabolism. So far, we have reported the following; 1) G4 is a target of cognitive function therapy for ATR-X intellectual disability syndrome, in which mutations are found in a G4 binding protein ATRX. 2) G4 is formed in heterochromatin depending on neuronal development. 3) G4 promotes prionoids in a CGG triplet repeat disease, Fragile X-associated tremor/ataxia syndrome (FXTAS). 4) 5-aminolevulinic acid is a potential candidate drug for treating some neurological diseases through the G4 binding ability. In this review, we summarized the significant roles of G4 in neurological diseases.
