Neuronal actin cytoskeleton gain of function in the human brainResearch in context
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
Affiliations
Kinga Szigeti
State University of New York at Buffalo, 875 Ellicott St., Buffalo, NY, 14203, USA; Corresponding author.
Ivanna Ihnatovych
State University of New York at Buffalo, 875 Ellicott St., Buffalo, NY, 14203, USA
Nicolás Rosas
State University of New York at Buffalo, 875 Ellicott St., Buffalo, NY, 14203, USA; Instituto de Investigaciones Biotecnológicas, Escuela de Bio y Nanotecnologías (EByN), Universidad Nacional de San Martín (UNSAM) – Consejo Nacional de, Investigaciones Científicas y Técnicas (CONICET), San Martín, Buenos Aires, Argentina
Ryu P. Dorn
State University of New York at Buffalo, 875 Ellicott St., Buffalo, NY, 14203, USA
Emily Notari
State University of New York at Buffalo, 875 Ellicott St., Buffalo, NY, 14203, USA
Eduardo Cortes Gomez
Roswell Park Comprehensive Cancer Center, 665 Elm St, Buffalo, NY 14203, USA
Muye He
State University of New York at Buffalo, 875 Ellicott St., Buffalo, NY, 14203, USA
Ivan Maly
State University of New York at Buffalo, 875 Ellicott St., Buffalo, NY, 14203, USA
Shreyas Prasad
State University of New York at Buffalo, 875 Ellicott St., Buffalo, NY, 14203, USA
Erik Nimmer
State University of New York at Buffalo, 875 Ellicott St., Buffalo, NY, 14203, USA
Yuna Heo
State University of New York at Buffalo, 875 Ellicott St., Buffalo, NY, 14203, USA
Beata Fuchsova
Instituto de Investigaciones Biotecnológicas, Escuela de Bio y Nanotecnologías (EByN), Universidad Nacional de San Martín (UNSAM) – Consejo Nacional de, Investigaciones Científicas y Técnicas (CONICET), San Martín, Buenos Aires, Argentina
David A. Bennett
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA
Wilma A. Hofmann
State University of New York at Buffalo, 875 Ellicott St., Buffalo, NY, 14203, USA
Arnd Pralle
State University of New York at Buffalo, 875 Ellicott St., Buffalo, NY, 14203, USA
Yongho Bae
State University of New York at Buffalo, 875 Ellicott St., Buffalo, NY, 14203, USA
Jianmin Wang
Roswell Park Comprehensive Cancer Center, 665 Elm St, Buffalo, NY 14203, USA
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.
