Portal de Periódicos da CAPES

Down syndrome DSCR1 causes spine pathology via the Fragile X-related protein FMRP

2012; Springer Nature; Volume: 31; Issue: 18 Linguagem: Inglês

10.1038/emboj.2012.239

1460-2075

Francesco Roselli,

Down syndrome and intellectual disability research

Have you seen?21 August 2012free access Down syndrome DSCR1 causes spine pathology via the Fragile X-related protein FMRP Francesco Roselli Corresponding Author Francesco Roselli Friedrich Miescher Institute for Biological Research, Basel, Switzerland Search for more papers by this author Francesco Roselli Corresponding Author Francesco Roselli Friedrich Miescher Institute for Biological Research, Basel, Switzerland Search for more papers by this author Author Information Francesco Roselli 1 1Friedrich Miescher Institute for Biological Research, Basel, Switzerland *Correspondence to: [email protected] The EMBO Journal (2012)31:3647-3649https://doi.org/10.1038/emboj.2012.239 There is an Article (September 2012) associated with this Have you seen?. PDFDownload PDF of article text and main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info A new study by Wang et al (2012) published in The EMBO Journal reports that the Down Syndrome Critical Region 1 (DSCR1) protein interacts with the Fragile X-related protein (FMRP) to regulate spine morphology and local protein synthesis. These findings highlight a convergence of Down syndrome (DS) and Fragile X pathogenic pathways, and provide insights on potential therapeutic approaches. DS is among the most common causes of intellectual disability of genetic origin. It is caused by the triplication of chromosome 21 (HSA21q), and is clinically characterized by phenotypes affecting multiple organs and systems, with prominent cognitive impairments. Although the chromosomal region 21q contains >350 genes, only a few of them have been linked to specific features of DS. With respect to intellectual disability, the analysis of partial triplications has pinpointed a number of DS critical regions, whose genes are involved in brain function (Patterson, 2009). Studies in transgenic mice and in human samples have uncovered a number of synaptic features disrupted in DS: spine densities are reduced, spines display abnormally large bulbous heads (Wang et al, 2012) and synaptic plasticity is altered. HSAq21 genes involved in synaptic physiology are therefore attractive candidates to account for intellectual disability in DS. Among them, DSCR1 (also known as RCAN1) is strongly expressed in the brain and its overexpression or knockout causes memory impairment and LTP derangement in mice. DSCR1 is a negative regulator of calcineurin phosphatase and, as such, has been implicated in a large number of functions both in and outside the CNS; however, the mechanisms linking DSCR1 to intellectual disability have not been identified unambiguously. Wang et al (2012) now show that DSCR1 interacts with, regulates and exerts its effects via the Fragile X mental retardation protein (FMRP). This remarkable finding reveals that two major causes of intellectual disability converge onto the regulation of local protein synthesis at synapses. Fmr1 gene is targeted by a triplet-expansion mutation that, by effectively preventing its transcription, causes the Fragile X syndrome (FXS, the most common cause of autism). FMRP is an RNA binding protein enriched at synapses. It regulates the transport of a subgroup of mRNAs coding for synaptic proteins, and, upon phosphorylation, reversibly represses their translation by recruiting the RISC and microRNAs (Muddashetty et al, 2011). In the absence of FMRP, protein translation goes on unchecked in synapses causing amplified LTD after mGluR activation and abnormally thin spine morphologies (Osterweil et al, 2010). In their study, Wang et al (2012) exploit genetic models, RNA interference and biochemical tools to demonstrate the genetic and functional interaction of DSCR1 and fmr1 in spine morphogenesis. The study first investigated the role of the two proteins on spine density and morphology. Overexpression of DSRC1 increased spine size and density, and that a 50% decrease in FMRP effectively rescued this phenotype. On the other hand, knockdown of either DSCR1 or fmr1 decreased spine size and density; and loss of both DSRC1 and FMRP did not aggravate this phenotype. Thus, while DSCR1 overexpression is compensated by fmr1 knockout, DSCR1 knockout occluded any further effect of fmr1 knockout. Since the actin cytoskeleton plays a prominent role in spine morphology, the actin-binding protein cofilin was a natural target of investigation to link DSCR1 to deranged spine structure. Dephosphorylated cofilin severs actin filaments and promote actin turnover, driving the formation of thin spines; phosphorylation blocks cofilin function and high level of phospho-cofilin results in the build-up of actin filaments, leading to increased spine size (Hotulainen et al, 2009). Consistent with morphological findings, phospho-cofilin level was upregulated by DSCR1 overexpression and, reciprocally, was downregulated by DSCR1 knockout. Cofilin phosphorylation is reversed by calcineurin, thus DSCR1 may modulate phospho-cofilin level by directly affecting calcineurin activity. However, FMRP decrease rescues DSCR1-induced phospho-cofilin upregulation, suggesting that local protein synthesis plays a major role in DSCR1-induced actin cytoskeleton remodelling. Wang et al (2012) elegantly explore DSCR1 effects on synaptic protein synthesis exploiting a Dendra-based reporter targeted to spines. By photoconverting Dendra before BDNF application, any newly (i.e., not photoconverted) synthesized fluorescent protein could be identified and quantified with high spatial accuracy. In contrast to conclusions from previous reports (Osterweil et al, 2010), basal translation rates in DSCR1 or fmr1 knockout mice were normal; this discrepancy may be due to the intrinsically lower sensitivity of the imaging approach compared to metabolic labelling methods, or to some peculiarities in reporter design. By contrast, DSCR1 overexpression greatly enhanced BDNF-induced protein synthesis, whereas DSCR1 knockout completely abolished the effects of BDNF. Interestingly, FMRP knockdown did not modulate DSCR1-enhanced protein synthesis, indicating that overexpression of DSCR1 is sufficient to occlude any further stimulation of local synthesis. Nevertheless, FMRP knockdown did shorten the duration of protein synthesis, supporting a role of FMRP in regulating not only translation rates but also the local availability of mRNAs. Mechanistically, DSCR1 is shown to interact directly with phosphorylated FMRP, but not with the unphosphorylated protein. DSCR1 inhibits calcineurin activity, thus increasing phospho-FMRP level and repressing translation (Figure 1A). DSCR1 phosphorylation, on the other hand, promotes activation of calcineurin. Activated calcineurin would then dephosphorylates both FMRP (causing the dissociation of the DSCR1–FMRP complex and the upregulation of translation; Figure 1B) and its own activator DSCR1 (closing a negative feedback loop). Figure 1.DSCR1 regulates mRNA translation at synapses through FMRP. (A) At rest, DSCR1 inhibits calcineurin that, in turn, does not dephosphorylate FMRP. Both mGluR5 and mTOR signalling cascades contribute to regulate FMRP phosphorylation; in its phosphorylated form, FMRP depresses mRNA translation. (B) Upon BDNF application, DSCR1 is phosphorylated and shifts to activate calcineurin, which efficiently dephosphorylates FMRP, relieving its inhibitory effect on mRNA translation. Download figure Download PowerPoint Intriguingly, FMRP knockout can rescue synaptic plasticity and behavioural impairment also in the Tsc2+/− mouse, a model of intellectual disability associated with tuberous sclerosis. Despite mTOR activity upregulation, synaptic protein synthesis is reduced in Tsc2+/− neurons (possibly because of FMRP hyperphosphorylation; Figure 1A) but it is restored to normal levels by fmr1 knockout (Auerbach et al, 2011). Thus, DSCR1 and Tsc2+/− transgenic mice display a similar FMRP-dependent downregulation of protein synthesis at synapses; in both cases, FMRP phosphorylation is critical in repressing translation. In contrast, if the FXS FMRP is strongly reduced and protein synthesis is constitutively upregulated. Therefore, altered local protein synthesis (either increase or decrease) emerges as a key player in the pathophysiology of intellectual disabilities. The convergence of DSCR1 and Tsc2 on FMRP suggests potential therapeutic interventions. In Tcs2+/− mice, mGluR5-positive allosteric modulators restore synaptic protein synthesis and ameliorate memory impairment (Auerbach et al, 2011). Furthermore, inhibition of overactive mTOR by rapamycin also improves electrophysiological and behavioural readouts in Tcs2 mice (Ehninger et al, 2008). On the other hand, in fmr1 knockout mice, mGluR5 antagonists repress deregulated protein synthesis and reverse behavioural abnormalities (Michalon et al, 2012). Since deregulated protein synthesis is also a major consequence of DSCR1 downregulation, compounds targeting mGluR5 and mTOR may prove equally beneficial. However, the overexpression of DSCR1 may result in both strong suppression of protein synthesis at rest and in excessive synthesis upon stimulation; the contribution of these two processes to the derangement of synaptic physiology deserves further investigations. Additional phenotypes resulting from DSCR1 overexpression have been described, including reduced neuronal density, defective neurogenesis and altered neuronal Ca2+ dynamics (Martin et al, 2012); the contribution of these phenotypes to the pathogenesis of intellectual disability and the involvement of FMRP remain to be elucidated. A growing number of autistic disorders have been linked to mutations in synaptic scaffold proteins (e.g., Shank and SAPAP proteins). Several of these proteins are regulated by local translation and may be critically affected by the DSCR1–FMRP pathway. Recently, fmr1 knockout was found to result in the disruption of the interaction of mGluR5 with Shank-interacting scaffold protein Homer. It is therefore conceivable that further convergences of pathogenic pathways may be uncovered in the near future. For the time being, Wang et al (2012) provide a critical step towards the integration of different genetic causes of intellectual disability into a single, unified pathogenic model. Conflict of Interest The author declares that he has no conflict of interest. References Auerbach BD, Osterweil EK, Bear MF (2011) Mutations causing syndromic autism define an axis of synaptic pathophysiology. Nature 480: 63–68CrossrefCASPubMedWeb of Science®Google Scholar Hotulainen P, Llano O, Smirnov S, Tanhuanpää K, Faix J, Rivera C, Lappalainen P (2009) Defining mechanisms of actin polymerization and depolymerization during dendritic spine morphogenesis. J Cell Biol 185: 323–339CrossrefCASPubMedWeb of Science®Google Scholar Ehninger D, Han S, Shilyansky C, Zhou Y, Li W, Kwiatkowski DJ, Ramesh V, Silva AJ (2008) Reversal of learning deficits in a Tsc2+/− mouse model of tuberous sclerosis. Nat Med 14: 843–848CrossrefCASPubMedWeb of Science®Google Scholar Martin KR, Corlett A, Dubach D, Mustafa T, Coleman HA, Parkington HC, Merson TD, Bourne JA, Porta S, Arbonés ML, Finkelstein DI, Pritchard MA (2012) Over-expression of RCAN1 causes Down syndrome-like hippocampal deficits that alter learning and memory. Hum Mol Genet 21: 3025–3041CrossrefCASPubMedWeb of Science®Google Scholar Michalon A, Sidorov M, Ballard TM, Ozmen L, Spooren W, Wettstein JG, Jaeschke G, Bear MF, Lindemann L (2012) Chronic pharmacological mGlu5 inhibition corrects fragile X in adult mice. Neuron 74: 49–56CrossrefCASPubMedWeb of Science®Google Scholar Muddashetty RS, Nalavadi VC, Gross C, Yao X, Xing L, Laur O, Warren ST, Bassell GJ (2011) Reversible inhibition of PSD-95 mRNA translation by miR-125a, FMRP phosphorylation, and mGluR signaling. Mol Cell 42: 673–688CrossrefCASPubMedWeb of Science®Google Scholar Osterweil EK, Krueger DD, Reinhold K, Bear MF (2010) Hypersensitivity to mGluR5 and ERK1/2 leads to excessive protein synthesis in the hippocampus of a mouse model of fragile X syndrome. J Neurosci 30: 15616–15627CrossrefCASPubMedWeb of Science®Google Scholar Patterson D (2009) Molecular genetic analysis of Down syndrome. Hum Genet 126: 195–214CrossrefCASPubMedWeb of Science®Google Scholar Ronesi JA, Collins KA, Hays SA, Tsai NP, Guo W, Birnbaum SG, Hu JH, Worley PF, Gibson JR, Huber KM (2012) Disrupted Homer scaffolds mediate abnormal mGluR5 function in a mouse model of fragile X syndrome. Nat Neurosci 15: 431–440CrossrefCASPubMedWeb of Science®Google Scholar Wang W, Zhu JZ, Chang KT, Min K-T (2012) DSCR1 interacts with FMRP and is required for spine morphogenesis and local protein synthesis. EMBO J 31: 3655–3666Wiley Online LibraryCASPubMedWeb of Science®Google Scholar Previous ArticleNext Article Read MoreAbout the coverClose modalView large imageVolume 31,Issue 18,September 12, 2012Soap bubbles in a Petri dish - This image, one of the top-scoring submissions to the EMBO Journal Cover Contest 2012, was taken by Viktor Sykora, a scientific researcher and photographer who works at the First Faculty of Medicine of Charles University in Prague. Visit his online galleries at http://www.viktorphoto.eu. Volume 31Issue 1812 September 2012In this issue FiguresReferencesRelatedDetailsLoading ...