2023-09-18 バッファロー大学(UB)
◆遺伝子の活性形態によって、アルファ7受容体を標的とする多くの薬物の効果が変化する可能性があり、これによりアルツハイマー病のリスクが高まる可能性がある一方、治療法の効果が低下する可能性も示唆されています。この研究は、神経科学研究が動物モデルに依存している問題を指摘し、ヒトに特有の遺伝子に関する研究の重要性を強調しています。
<関連情報>
- https://www.buffalo.edu/news/releases/2023/09/UB-discovers-gene-may-protect-against-neurodegeneration.html
- https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(23)00290-6/fulltext
ヒト脳における神経細胞骨格の機能獲得 Neuronal actin cytoskeleton gain of function in the human brain
Kinga Szigeti,Ivanna Ihnatovych,Nicolás Rosas,Ryu P. Dorn,Emily Notari,Eduardo Cortes Gomez,Muye He,Ivan Maly,Shreyas Prasad,Erik Nimmer,Yuna Heo,Beata Fuchsova,David A. Bennett,Wilma A. Hofmann,Arnd Pralle,Yongho Bae,Jianmin Wang
eBiomedicine Published:July 28, 2023
DOI:https://doi.org/10.1016/j.ebiom.2023.10472
Summary
Background
While advancements in imaging techniques have led to major strides in deciphering the human brain, successful interventions are elusive and represent some of the most persistent translational gaps in medicine. Human restricted CHRFAM7A has been associated with neuropsychiatric disorders.
Methods
The physiological role of CHRFAM7A in human brain is explored using multiomics approach on 600 post mortem human brain tissue samples. The emerging pathways and mechanistic hypotheses are tested and validated in an isogenic hiPSC model of CHRFAM7A knock-in medial ganglionic eminence progenitors and neurons.
Findings
CHRFAM7A is identified as a modulator of intracellular calcium dynamics and an upstream regulator of Rac1. Rac1 activation re-designs the actin cytoskeleton leading to dynamic actin driven remodeling of membrane protrusion and a switch from filopodia to lamellipodia. The reinforced cytoskeleton leads to an advantage to tolerate stiffer mechanical properties of the extracellular environment.
Interpretation
CHRFAM7A modifies the actin cytoskeleton to a more dynamic and stiffness resistant state in an α7nAChR dependent manner. CHRFAM7A may facilitate neuronal adaptation to changes in the brain environment in physiological and pathological conditions contributing to risk or recovery. Understanding how CHRFAM7A affects human brain requires human studies in the areas of memory formation and erasure, cognitive reserve, and neuronal plasticity.
Funding
This work is supported in part by the Community Foundation for Greater Buffalo (Kinga Szigeti). Also, in part by the International Society for Neurochemistry (ISN) and The Company of Biologists (Nicolas Rosas). ROSMAP is supported by NIA grants P30AG10161, P30AG72975, R01AG15819, R01AG17917. U01AG46152, and U01AG61356.
