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- Title
Elevated progranulin contributes to synaptic and learning deficit due to loss of fragile X mental retardation protein.
- Authors
Kun Zhang; Yu-jiao Li; Yanyan Guo; Kai-yin Zheng; Qi Yang; Le Yang; Xin-shang Wang; Qian Song; Tao Chen; Min Zhuo; Ming-gao Zhao; Zhang, Kun; Li, Yu-Jiao; Guo, Yanyan; Zheng, Kai-Yin; Yang, Qi; Yang, Le; Wang, Xin-Shang; Song, Qian; Chen, Tao
- Abstract
Fragile X syndrome is an inheritable form of intellectual disability caused by loss of fragile X mental retardation protein (FMRP, encoded by the FMR1 gene). Absence of FMRP caused overexpression of progranulin (PGRN, encoded by GRN), a putative tumour necrosis factor receptor ligand. In the present study, we found that progranulin mRNA and protein were upregulated in the medial prefrontal cortex of Fmr1 knock-out mice. In Fmr1 knock-out mice, elevated progranulin caused insufficient dendritic spine pruning and late-phase long-term potentiation in the medial prefrontal cortex of Fmr1 knock-out mice. Partial progranulin knock-down restored spine morphology and reversed behavioural deficits, including impaired fear memory, hyperactivity, and motor inflexibility in Fmr1 knock-out mice. Progranulin increased levels of phosphorylated glutamate ionotropic receptor GluA1 and nuclear factor kappa B in cultured wild-type neurons. Tumour necrosis factor receptor 2 antibody perfusion blocked the effects of progranulin on GluA1 phosphorylation; this result indicates that tumour necrosis factor receptor 2 is required for progranulin-mediated GluA1 phosphorylation and late-phase long-term potentiation expression. However, high basal level of progranulin in Fmr1 knock-out mice prevented further facilitation of synaptic plasticity by exogenous progranulin. Partial downregulation of progranulin or tumour necrosis factor receptor 2/nuclear factor kappa B signalling restored synaptic plasticity and memory deficits in Fmr1 knock-out mice. These findings suggest that elevated PGRN is linked to cognitive deficits of fragile X syndrome, and the progranulin/tumour necrosis factor receptor 2 signalling pathway may be a putative therapeutic target for improving cognitive deficits in fragile X syndrome.
- Subjects
PROGRANULIN; FRAGILE X syndrome; TUMOR necrosis factors; MESSENGER RNA; LABORATORY mice; THERAPEUTICS; RNA metabolism; ANIMAL behavior; ANIMAL experimentation; ANIMALS; CELL culture; CELL receptors; CELLULAR signal transduction; FLUORESCENT antibody technique; FRONTAL lobe; GENETIC techniques; GROWTH factors; IMMUNOGLOBULINS; LEARNING; MICE; NERVE tissue proteins; NERVOUS system; NEURONS; NEUROPLASTICITY; PHOSPHORYLATION; WESTERN immunoblotting; DNA-binding proteins
- Publication
Brain: A Journal of Neurology, 2017, Vol 140, Issue 12, p3215
- ISSN
0006-8950
- Publication type
journal article
- DOI
10.1093/brain/awx265