NEUROBIOLOGY MicroRNA Pathway, Synaptic Function, and Disease

Fragile X-related protein (FMRP) is an RNA-binding protein whose loss in fragile X syndrome results in mental retardation. When incorporated into a messenger ribonucleoprotein, it is thought to associate with ribosomes and to regulate protein synthesis locally in neurons. The Drosophila ortholog of FMRP associates with an RNA-induced silencing complex (RISC) that includes a protein called Argonaute 2 to control the processing of microRNAs (miRNAs). These miRNAs are short, noncoding RNAs that target mRNA for destruction. However, a link between the effect of FMRP on miRNAs and fragile X syndrome has not been clear. Jin et al. report that mammalian FMRP also interacts with the miRNA processing machinery in normal human cells. MiRNAs and possible precursor transcripts were detected in immunoprecipitates of FMRP from normal human cells but not from cells of fragile X patients. Activity of Dicer, an RNAse that processes miRNA precursors, and the mammalian Argonaute protein eIF2C2 were also present in FMRP immunoprecipitates from normal human cells only. Overexpression of FMRP in the Drosophila eye results in apoptosis. However, additional reduction of Argonaute 1 suppressed this phenotype, indicating a genetic interaction. The authors propose that FMRP may exert translational suppression through associated miRNAs and RISC complexes on target mRNAs. Disruption of this mechanism in neurons could affect the local protein synthesis response to synaptic stimulation and affect neural development and maintenance.

P. Jin, D. C. Zarnescu, S. Ceman, M. Nakamoto, J. Mowrey, T. A. Jongens, D. L. Nelson, K. Moses, S. T. Warren, Biochemical and genetic interaction between the fragile X mental retardation protein and the microRNA pathway. Nature Neurosci. 7, 113-117 (2004). [Online Journal]