Title: Elevated levels of FMRP-target MAP1B impair human and mouse neuronal development and mouse social behaviors via autophagy pathway
Legend: A schematic model illustrating how MAP1B-EE impairs neuronal development and social behaviors: In healthy neurons, there is an equilibrium between MAP1B-bonded LC3-I and freely available LC3-I. The freely available LC3-I can interact with ATG proteins that add phospholipids to LC3-I to form LC3-II (lipidation) and initiate the autophagosome formation. In neurons with MAP1B-EE, high levels of MAP1B bind and sequester cellular LC3-I and reduce the amount of LC3-I that can interact with ATGs leading to reduced autophagosome formation and impaired autophagy. Rapamycin increases LC3-II levels through inhibiting mTOR signaling. In FXS and ASD neurons with elevated MAP1B levels, both genetic reduction of MAP1B and treatment with rapamycin can rescue autophagy therefore rescue morphological and electrophysiological deficits.
Citation: Guo Y (Kristy), Shen M, Dong Q, Mendez-Albelo NM, Le J, Li M, Huang SX, Jarzembowski ED, Schoeller KA, M.E. S, Sirois CL, Horner VL, Sousa AMM, Gao Y, Birth Defects Research Laboratory, Levine JE, Wang D, Chang Q, Zhao, X. . Elevated levels of FMRP-target MAP1B impair neuronal development and social behaviors via autophagy pathway”. . Nature Communications (in press)
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) remain 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.
About the Lab: The Zhao Lab is located at the Waisman Center of University of Wisconsin-Madison, our laboratory is part of the Department of Neuroscience and Stem Cells and Regenerative Medicine Center. We strive to adapt, develop, and integrate state-of-art approaches to investigate the molecular mechanisms underlying neurogenesis and neuronal development.
About the Investigator: Xinyu Zhao, PhD
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