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

Yu Guo, Minjie Shen, Qiping Dong, Natasha M. Méndez-Albelo, Sabrina X. Huang, Carissa L. Sirois, Jonathan Le, Meng Li, Ezra D. Jarzembowski, Keegan A. Schoeller, Michael E. Stockton, Vanessa L. Horner, André M. M. Sousa, Yu Gao, Jon E. Levine, Daifeng Wang, Qiang Chang and Xinyu Zhao ()
Additional contact information
Yu Guo: University of Wisconsin-Madison
Minjie Shen: University of Wisconsin-Madison
Qiping Dong: University of Wisconsin-Madison
Natasha M. Méndez-Albelo: University of Wisconsin-Madison
Sabrina X. Huang: University of Wisconsin-Madison
Carissa L. Sirois: University of Wisconsin-Madison
Jonathan Le: University of Wisconsin-Madison
Meng Li: University of Wisconsin-Madison
Ezra D. Jarzembowski: University of Wisconsin-Madison
Keegan A. Schoeller: University of Wisconsin-Madison
Michael E. Stockton: University of Wisconsin-Madison
Vanessa L. Horner: University of Wisconsin-Madison
André M. M. Sousa: University of Wisconsin-Madison
Yu Gao: University of Wisconsin-Madison
Jon E. Levine: University of Wisconsin-Madison
Daifeng Wang: University of Wisconsin-Madison
Qiang Chang: University of Wisconsin-Madison
Xinyu Zhao: University of Wisconsin-Madison

Nature Communications, 2023, vol. 14, issue 1, 1-23

Abstract: Abstract Fragile 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.

Date: 2023
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DOI: 10.1038/s41467-023-39337-0

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