Inhibition of SNAP25 expression by HIV‐1 Tat involves the activity of mir‐128a

Abstract

MicroRNAs (miRs) are short endogenous RNAs that regulate gene expression by incomplete pairing with messenger RNAs. An increasing number of studies show that mammalian microRNAs play fundamental roles in various aspects of cellular function including differentiation, proliferation, and cell death. Recent findings demonstrating the presence of microRNAs in mature neuronal dendrites suggest their possible involvement in controlling local protein translation and synaptic function. HIV-1 Encephalopathy (HIVE) is a manifestation of HIV-1 infection that often results in neuronal damage and dysfunction. While neurons are rarely, if ever, infected by HIV-1, they are exposed to cytotoxic viral and cellular factors including the HIV-1 transactivating factor Tat. In this study, we show that Tat deregulates expression levels of selected microRNAs, including the neuronal mir-128, in primary cortical neurons. We further show that mir-128a inhibits expression of the pre-synaptic protein SNAP25, whereas the anti-mir-128a partially restores Tat/mir-128a-induced downregulation of SNAP25 expression. Altogether, our data provide a novel mechanism by which HIV-Tat perturbs neuronal activity.MicroRNAs (miRNAs, miRs) are a growing class of short non-coding RNAs that control posttranscriptional gene expression (Ke et al., 2003;Lai, 2003). Mature microRNA derive from longer transcripts (pri-miRs) which are processed to shorter hairpin precursors (pre-miRs) by the action of Drosha enzyme (Lee et al., 2003). The 70-nucleotides precursors are exported to the cytoplasm where they are cleaved by Dicer to produce mature 19-22 nucleotides microRNA, which enter RNA-induced silencing complex (RISC;Hutvagner et al., 2001;Ketting et al., 2001). Translational silencing by the RISC complex appears to regulate a wide variety of cellular and developmental processes (Du and Zamore, 2005;Hwang and Mendell, 2006). An increasing number of studies have shown the presence of microRNAs in the central nervous system (CNS) and their importance for neuronal development (Klein et al., 2005;Cao et al., 2006). As protein synthesis in neurons occurs not only in the cell body but also in axons and dendrites, the enrichment of microRNAs in the neuronal processes (Tai and Schuman, 2006) suggests a possible action of dendritic microRNAs in regulating synaptic function (Kim et al., 2004(Kim et al., , 2005, as well as spine development (Schratt et al., 2006 Synaptic vesicles are critical regulators of pre-synaptic events that are required for proper neurotransmission, including organelle transport, interaction with cytoskeleton, uptake and storage of low molecular weight molecules, and membrane fusion for exo-and endocytosis (reviewed by Burre and Volknandt (2007)). Key regulators of membrane fusion are the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins (reviewed by Salaun et al. (2004)). Among them, synaptosome associated protein of 25 kDa (SNAP25) is associated with the cell membrane.Human immunodeficiency virus 1 (HIV-1)...

HIV-1 Tat Protein Promotes Neuronal Dysfunction through Disruption of MicroRNAs

“…Reciprocally, HIV-1 was shown to affect the levels of several miRNAs to change their expression profile (30). Tat protein was also shown to deregulate expression levels of selected miRNAs, including the neuronal mir-128, in primary cortical neurons (31).…”

Anti-Argonaute RIP-Chip shows that miRNA transfections alter global patterns of mRNA recruitment to microribonucleoprotein complexes

“…Interestingly, there is an increase in miR-128 expression in the Alzheimer's disease hippocampus relative to control hippocampus (Lukiw 2007). Prior studies have provided evidence that miR-128 targets E2F3A, BMI-1, NTRK3, and SNAP25 mRNAs (Eletto et al 2008;Godlewski et al 2008;MuinosGimeno et al 2009;Zhang et al 2009). Our results do not provide direct confirmation for those interactions in these cultured cells; however, most of these genes are expressed only at low levels in cultured H4 cells.…”

Allele variants in functional MicroRNA target sites of the neurotrophin-3 receptor gene (NTRK3) as susceptibility factors for anxiety disorders

“…In fact, miR-485-3p is a brain enriched miRNA that is expressed in the adult hippocampus and cerebellum [Betel, et al, 2008], miR-765 is located in the intron of ARHGEF11, a gene highly expressed in brain that has been described to have a role as modulator in glutamatergic synapses [Jackson, et al, 2001]. More interestingly, miR-128 has been implicated in the differentiation of neurons [Smirnova, et al, 2005] and, very recently, in the inhibition of the pre-synaptic protein SNAP25 [Eletto, et al, 2008] fact that strengthens the importance of the miR-128 mediated regulation of NTRK3 in the context of synaptic plasticity. In the case of miR-509, a miRNA that shares the target site of miR-128, its expression has been observed to be restricted to testis [Betel, et al, 2008], that could suggest tissue dependent regulation of NTRK3 at this site.…”