前臨床試験により、脳の免疫細胞がASDや知的障害の新たな創薬ターゲットになる可能性があることが判明 Preclinical study reveals that immune cells in the brain could be possible new drug targets for ASD and intellectual disability
2022-06-30 バッファロー大学(UB)
これらの遺伝子に変異が生じると、免疫応答遺伝子やミクログリアと呼ばれる脳の免疫細胞の一種の遺伝子が異常に活性化され、過剰発現することが明らかになった。
UBの科学者たちは、研究対象となった2つの遺伝子の変異がミクログリアを活性化し、脳内の免疫遺伝子を過剰に発現させることを発見した。その結果、ASD/IDの特徴である脳内のシナプスの機能異常が生じるという仮説が立てられた。
研究では、ASD/ID患者の死後脳組織のほか、ADNPとPOGZを低分子干渉RNAのウイルス投与によってサイレンシングしたマウスを用いた研究が行われた。これらのマウスは、空間記憶、物体認識記憶、長期記憶などの認知タスクのパフォーマンスに障害を示した。
<関連情報>
- https://www.buffalo.edu/news/releases/2022/06/027.html
- https://academic.oup.com/brain/advance-article-abstract/doi/10.1093/brain/awac152/6619512
神経発達障害における高リスク因子ADNPとPOGZの収束メカニズム A convergent mechanism of high risk factors ADNP and POGZ in neurodevelopmental disorders
Megan Conrow-Graham, Jamal B Williams, Jennifer Martin, Ping Zhong, Qing Cao, Benjamin Rein, Zhen Yan
Brain Published::01 July 2022
DOI:https://doi.org/10.1093/brain/awac152
Abstract
ADNP and POGZ are two top-ranking risk factors for autism spectrum disorder and intellectual disability, but how they are linked to these neurodevelopmental disorders is largely unknown. Both ADNP and POGZ are chromatin regulators, which could profoundly affect gene transcription and cellular function in the brain. Using post-mortem tissue from patients with autism spectrum disorder, we found diminished expression of ADNP and POGZ in the prefrontal cortex, a region highly implicated in neurodevelopmental disorders. To understand the functional role of these neurodevelopmental disorder risk factors, we used viral-based gene transfer to investigate how Adnp or Pogz deficiency in mouse prefrontal cortex affects behavioural, transcriptomic and synaptic function. Mice with prefrontal cortex deficiency of Adnp or Pogz exhibited specific impairment of cognitive task performance. RNA-sequencing revealed that Adnp or Pogz deficiency induced prominent upregulation of overlapping genes enriched in neuroinflammation, similar to the elevation of pro-inflammatory genes in humans with neurodevelopmental disorders. Concomitantly, Adnp or Pogz deficiency led to the significant increase of pro-phagocytic microglial activation in prefrontal cortex, as well as the significant decrease of glutamatergic transmission and postsynaptic protein expression. These findings have uncovered the convergent functions of two top risk factors for autism spectrum disorder and intellectual disability in prefrontal cortex, providing a mechanism linking chromatin, transcriptional and synaptic dysregulation to cognitive deficits associated with neurodevelopmental disorders.
