Elevated levels of FMRP-target MAP1B impair human and mouse neuronal development and mouse social behaviors via autophagy pathway

Author:

Guo YuORCID,Shen MinjieORCID,Dong Qiping,Méndez-Albelo Natasha M.ORCID,Huang Sabrina X.,Sirois Carissa L.,Le Jonathan,Li Meng,Jarzembowski Ezra D.,Schoeller Keegan A.ORCID,Stockton Michael E.,Horner Vanessa L.,Sousa André M. M.ORCID,Gao YuORCID,Glass Ian A.,Doherty Dan,Levine Jon E.ORCID,Wang DaifengORCID,Chang QiangORCID,Zhao XinyuORCID,

Abstract

AbstractFragile X messenger ribonucleoprotein 1 protein (FMRP) binds many mRNA targets in the brain. The contribution of these targets to fragile X syndrome (FXS) and related autism spectrum disorder (ASD) remains unclear. Here, we show that FMRP deficiency leads to elevated microtubule-associated protein 1B (MAP1B) in developing human and non-human primate cortical neurons. Targeted MAP1B gene activation in healthy human neurons or MAP1B gene triplication in ASD patient-derived neurons inhibit morphological and physiological maturation. Activation of Map1b in adult male mouse prefrontal cortex excitatory neurons impairs social behaviors. We show that elevated MAP1B sequesters components of autophagy and reduces autophagosome formation. Both MAP1B knockdown and autophagy activation rescue deficits of both ASD and FXS patients’ neurons and FMRP-deficient neurons in ex vivo human brain tissue. Our study demonstrates conserved FMRP regulation of MAP1B in primate neurons and establishes a causal link between MAP1B elevation and deficits of FXS and ASD.

Funder

U.S. Department of Health & Human Services | NIH | National Institute of Mental Health

U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke

U.S. Department of Health & Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development

United States Department of Defense | United States Army | Army Medical Command | Congressionally Directed Medical Research Programs

Simons Foundation

Jenni and Kyle Professorship, Wisconsin Alumni Research Foundation, UW Vilas Mid-Career Award,

FRAXA Postdoctoral fellowship

U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences

SciMed scholarship

FRAXA Postdoctoral fellowship, Autism Science Foundation Postdoctoral fellowship, UW Stem Cell and Regenerative Medicine Center Postdoctoral fellowship,

Brain and Behavior Research Foundation

U.S. Department of Health & Human Services | NIH | NIH Office of the Director

Department of Communications, Energy and Natural Resources

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

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