Neuronal actin cytoskeleton gain of function in the human brain.

Humans Gain of Function Mutation Brain / metabolism Neurons / metabolism Actin Cytoskeleton / metabolism Actins / metabolism
Actin cytoskeleton CHRFAM7A Human brain Multiomics analysis iPSC

Journal

EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039

Informations de publication

Date de publication:
Sep 2023
Historique:
received: 10 02 2023
revised: 21 06 2023
accepted: 07 07 2023
medline: 18 9 2023
pubmed: 30 7 2023
entrez: 30 7 2023
Statut: ppublish

Résumé

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. 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. 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. 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. 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.

Sections du résumé

BACKGROUND 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 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 RESULTS
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 CONCLUSIONS
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 BACKGROUND
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.

Identifiants

DOI: 10.1016/j.ebiom.2023.104725 PMID: 37517100 PMC: PMC10404607
pubmed: 37517100
pii: S2352-3964(23)00290-6
doi: 10.1016/j.ebiom.2023.104725
pmc: PMC10404607
pii:
doi:

Substances chimiques

Actins 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

104725

Subventions

Organisme : NIA NIH HHS
ID : P30 AG010161
Pays : United States

Informations de copyright

Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests The authors declare no conflict of interest.

Auteurs

Kinga Szigeti (K)

State University of New York at Buffalo, 875 Ellicott St., Buffalo, NY, 14203, USA. Electronic address: szigeti@buffalo.edu.

Ivanna Ihnatovych (I)

State University of New York at Buffalo, 875 Ellicott St., Buffalo, NY, 14203, USA.

Nicolás Rosas (N)

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 (RP)

State University of New York at Buffalo, 875 Ellicott St., Buffalo, NY, 14203, USA.

Emily Notari (E)

State University of New York at Buffalo, 875 Ellicott St., Buffalo, NY, 14203, USA.

Eduardo Cortes Gomez (E)

Roswell Park Comprehensive Cancer Center, 665 Elm St, Buffalo, NY 14203, USA.

Muye He (M)

State University of New York at Buffalo, 875 Ellicott St., Buffalo, NY, 14203, USA.

Ivan Maly (I)

State University of New York at Buffalo, 875 Ellicott St., Buffalo, NY, 14203, USA.

Shreyas Prasad (S)

State University of New York at Buffalo, 875 Ellicott St., Buffalo, NY, 14203, USA.

Erik Nimmer (E)

State University of New York at Buffalo, 875 Ellicott St., Buffalo, NY, 14203, USA.

Yuna Heo (Y)

State University of New York at Buffalo, 875 Ellicott St., Buffalo, NY, 14203, USA.

Beata Fuchsova (B)

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 (DA)

Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.

Wilma A Hofmann (WA)

State University of New York at Buffalo, 875 Ellicott St., Buffalo, NY, 14203, USA.

Arnd Pralle (A)

State University of New York at Buffalo, 875 Ellicott St., Buffalo, NY, 14203, USA.

Yongho Bae (Y)

State University of New York at Buffalo, 875 Ellicott St., Buffalo, NY, 14203, USA.

Jianmin Wang (J)

Roswell Park Comprehensive Cancer Center, 665 Elm St, Buffalo, NY 14203, USA.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Neuronal actin cytoskeleton gain of function...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Mutation gain de fonction › Neuronal actin cytoskeleton gain of function...
questionsmedicales.fr › Système nerveux › Système nerveux central › Encéphale › Neuronal actin cytoskeleton gain of function...
questionsmedicales.fr › Cellules › Neurones › Neuronal actin cytoskeleton gain of function...
questionsmedicales.fr › Cellules › Structures cellulaires › Espace intracellulaire › Cytoplasme › Structures cytoplasmiques › Cytosquelette › Cytosquelette d'actine › Neuronal actin cytoskeleton gain of function...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines du cytosquelette › Protéines des microfilaments › Actines › Neuronal actin cytoskeleton gain of function...