Elevated levels of FMRP-target MAP1B impair human and mouse neuronal development and mouse social behaviors via autophagy pathway
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jun 26, 2023
- Source ID
- 10.1038/s41467-023-39337-0
Entities
People
- André M M Sousa
- Birth Defects Research Laboratory
- Carissa L. Sirois
- Daifeng Wang
- Dan Doherty
- Ezra D. Jarzembowski
- Ian A. Glass
- Jon E Levine
- Jonathan Le
- Keegan A. Schoeller
- Meng Li
- Michael E. Stockton
- Minjie Shen
- Natasha M. Méndez-Albelo
- Qiang Chang
- Qiping Dong
- Sabrina X. Huang
- Vanessa L. Horner
- Xinyu Zhao
- Yu Gao
- Yu Guo
Organizations
- Brain & Behavior Research Foundation
- Congressionally Directed Medical Research Programs
- Department of Climate, Energy and the Environment
- Eunice Kennedy Shriver National Institute of Child Health and Human Development
- National Institute of General Medical Sciences
- National Institute of Mental Health
- National Institute of Neurological Disorders and Stroke
- Office of the Director
- Simons Foundation
- United States Department of Health and Human Services