Growth-suppressor microRNAs mediate synaptic overgrowth and behavioral deficits in Fragile X mental retardation protein deficiency.

Autor:	Subramanian M; Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA., Mills WT 4th; Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA., Paranjpe MD; Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.; Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA., Onuchukwu US; Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA., Inamdar M; Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA., Maytin AR; Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA., Li X; Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA., Pomerantz JL; Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.; Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA., Meffert MK; Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.; Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Jazyk:	angličtina
Zdroj:	IScience [iScience] 2023 Dec 12; Vol. 27 (1), pp. 108676. Date of Electronic Publication: 2023 Dec 12 (Print Publication: 2024).
DOI:	10.1016/j.isci.2023.108676
Abstrakt:	Abnormal neuronal and synapse growth is a core pathology resulting from deficiency of the Fragile X mental retardation protein (FMRP), but molecular links underlying the excessive synthesis of key synaptic proteins remain incompletely defined. We find that basal brain levels of the growth suppressor let-7 microRNA (miRNA) family are selectively lowered in FMRP-deficient mice and activity-dependent let-7 downregulation is abrogated. Primary let-7 miRNA transcripts are not altered in FMRP-deficiency and posttranscriptional misregulation occurs downstream of MAPK pathway induction and elevation of Lin28a, a let-7 biogenesis inhibitor. Neonatal restoration of brain let-7 miRNAs corrects hallmarks of FMRP-deficiency, including dendritic spine overgrowth and social and cognitive behavioral deficits, in adult mice. Blockade of MAPK hyperactivation normalizes let-7 miRNA levels in both brain and peripheral blood plasma from Fmr1 KO mice. These results implicate dysregulated let-7 miRNA biogenesis in the pathogenesis of FMRP-deficiency, and highlight let-7 miRNA-based strategies for future biomarker and therapeutic development. Competing Interests: The authors declare no competing interests. (© 2023 The Author(s).)
Databáze:	MEDLINE
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