The Experts below are selected from a list of 12918 Experts worldwide ranked by ideXlab platform
Hervé Le Hir - One of the best experts on this subject based on the ideXlab platform.
-
A conserved structural element in the RNA helicase UPF1 regulates its catalytic activity in an isoform-specific manner
Nucleic Acids Research, 2018Co-Authors: Manjeera Gowravaram, Hervé Le Hir, Fabien Bonneau, Francesca Fiorini, Joanne Kanaan, Vincent Croquette, Vincent Maciej, Saurabh Raj, Sutapa ChakrabartiAbstract:The RNA helicase UPF1 is a key component of the nonsense mediated mRNA decay (NMD) pathway. Previous X-ray crystal structures of UPF1 elucidated the molecular mechanisms of its catalytic activity and regulation. In this study, we examine features of the UPF1 core and identify a structural element that adopts different conformations in the various nucleotide-and RNA-bound states of UPF1. We demonstrate, using biochemical and single molecule assays, that this structural element modulates UPF1 catalytic activity and thereby refer to it as the regulatory loop. Interestingly, there are two alternatively spliced isoforms of UPF1 in mammals which differ only in the lengths of their regulatory loops. The loop in isoform 1 (UPF1 1) is 11 residues longer than that of isoform 2. We find that this small insertion in UPF1 1 leads to a twofold increase in its translocation and ATPase activities. To determine the mechanistic basis of this differential catalytic activity, we have determined the X-ray crystal structure of the helicase core of UPF1 1 in its apo-state. Our results point toward a novel mechanism of regulation of RNA helicases, wherein alternative splicing leads to subtle structural rearrangements within the protein that are critical to modulate enzyme movements and catalytic activity.
-
HTLV-1 Tax plugs and freezes UPF1 helicase leading to nonsense-mediated mRNA decay inhibition
Nature Publishing Group, 2018Co-Authors: Francesca Fiorini, Hervé Le Hir, Jean-philippe Robin, Joanne Kanaan, Malgorzata Borowiak, Vincent Croquette, Pierre Jalinot, Vincent MocquetAbstract:UPF1 is a central protein in nonsense-mediated mRNA decay (NMD), but contribution of its RNA processivity to NMD is unclear. Here, the authors show how the retroviral Tax protein interacts with and inhibits UPF1, and demonstrate that UPF1’s translocase activity contributes to NMD
-
human UPF1 is a highly processive rna helicase and translocase with rnp remodelling activities
Nature Communications, 2015Co-Authors: Francesca Fiorini, Hervé Le Hir, Debjani Bagchi, Vincent CroquetteAbstract:UPF1 is a multifunctional helicase involved in various DNA- and RNA-related processes, including nonsense-mediated mRNA decay (NMD). Here the authors demonstrate that UPF1 is a highly processive ribonucleoprotein complex remodeler—a capability likely important for UPF1’s NMD function.
-
the human t lymphotropic virus type 1 tax protein inhibits nonsense mediated mrna decay by interacting with int6 eif3e and UPF1
Journal of Virology, 2012Co-Authors: Vincent Mocquet, Madeleine Duc Dodon, Julia Neusiedler, Francesca Rende, David Cluet, Jean-philippe Robin, Jean-michel Terme, Christelle Morris, Jürgen Wittmann, Hervé Le HirAbstract:In this report, we analyzed whether the degradation of mRNAs by the nonsense-mediated mRNA decay (NMD) pathway was affected in human T-lymphotropic virus type 1 (HTLV-1)-infected cells. This pathway was indeed strongly inhibited in C91PL, HUT102, and MT2 cells, and such an effect was also observed by the sole expression of the Tax protein in Jurkat and HeLa cells. In line with this activity, Tax binds INT6/EIF3E (here called INT6), which is a subunit of the translation initiation factor eukaryotic initiation factor 3 (eIF3) required for efficient NMD, as well as the NMD core factor upstream frameshift protein 1 (UPF1). It was also observed that Tax expression alters the morphology of processing bodies (P-bodies), the cytoplasmic structures which concentrate RNA degradation factors. The presence of UPF1 in these subcellular compartments was increased by Tax, whereas that of INT6 was decreased. In line with these effects, the level of the phosphorylated form of UPF1 was increased in the presence of Tax. Analysis of several mutants of the viral protein showed that the interaction with INT6 is necessary for NMD inhibition. The alteration of mRNA stability was observed to affect viral transcripts, such as that coding for the HTLV-1 basic leucine zipper factor (HBZ), and also several cellular mRNAs sensitive to the NMD pathway. Our data indicate that the effect of Tax on viral and cellular gene expression is not restricted to transcriptional control but can also involve posttranscriptional regulation.
-
molecular mechanisms for the rna dependent atpase activity of UPF1 and its regulation by upf2
Molecular Cell, 2011Co-Authors: Sutapa Chakrabarti, Hervé Le Hir, Fabien Bonneau, Francesca Fiorini, Uma Jayachandran, Claire Basquin, Silvia Domcke, Elena ContiAbstract:Summary UPF1 is a crucial factor in nonsense-mediated mRNA decay, the eukaryotic surveillance pathway that degrades mRNAs containing premature stop codons. The essential RNA-dependent ATPase activity of UPF1 is triggered by the formation of the surveillance complex with Upf2-Upf3. We report crystal structures of UPF1 in the presence and absence of the CH domain, captured in the transition state with ADP:AlF 4 − and RNA. In isolation, UPF1 clamps onto the RNA, enclosing it in a channel formed by both the catalytic and regulatory domains. Upon binding to Upf2, the regulatory CH domain of UPF1 undergoes a large conformational change, causing the catalytic helicase domain to bind RNA less extensively and triggering its helicase activity. Formation of the surveillance complex thus modifies the RNA binding properties and the catalytic activity of UPF1, causing it to switch from an RNA-clamping mode to an RNA-unwinding mode.
Lynne E. Maquat - One of the best experts on this subject based on the ideXlab platform.
-
UPF1 helicase promotes TSN-mediated miRNA decay
Genes & Development, 2017Co-Authors: Reyad A. Elbarbary, Omar Hedaya, Jason R. Myers, Keita Miyoshi, Lynne E. MaquatAbstract:While microRNAs (miRNAs) regulate the vast majority of protein-encoding transcripts, little is known about how miRNAs themselves are degraded. We recently described Tudor-staphylococcal/micrococcal-like nuclease (TSN)-mediated miRNA decay (TumiD) as a cellular pathway in which the nuclease TSN promotes the decay of miRNAs that contain CA and/or UA dinucleotides. While TSN-mediated degradation of either protein-free or AGO2-loaded miRNAs does not require the ATP-dependent RNA helicase UPF1 in vitro, we report here that cellular TumiD requires UPF1. Results from experiments using AGO2-loaded miRNAs in duplex with target mRNAs indicate that UPF1 can dissociate miRNAs from their mRNA targets, making the miRNAs susceptible to TumiD. miR-seq (deep sequencing of miRNAs) data reveal that the degradation of ∼50% of candidate TumiD targets in T24 human urinary bladder cancer cells is augmented by UPF1. We illustrate the physiological relevance by demonstrating that UPF1-augmented TumiD promotes the invasion of T24 cells in part by degrading anti-invasive miRNAs so as to up-regulate the expression of proinvasive proteins.
-
preservation of forelimb function by UPF1 gene therapy in a rat model of tdp 43 induced motor paralysis
Gene Therapy, 2015Co-Authors: K L Jackson, Lynne E. Maquat, R D Dayton, E A Orchard, D Ringe, G A Petsko, Shulin Ju, R L KleinAbstract:Preservation of forelimb function by UPF1 gene therapy in a rat model of TDP-43-induced motor paralysis
-
staufen2 functions in staufen1 mediated mrna decay by binding to itself and its paralog and promoting UPF1 helicase but not atpase activity
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Eonyoung Park, Michael L Gleghorn, Lynne E. MaquatAbstract:Staufen (STAU)1-mediated mRNA decay (SMD) is a posttranscriptional regulatory mechanism in mammals that degrades mRNAs harboring a STAU1-binding site (SBS) in their 3'-untranslated regions (3' UTRs). We show that SMD involves not only STAU1 but also its paralog STAU2. STAU2, like STAU1, is a double-stranded RNA-binding protein that interacts directly with the ATP-dependent RNA helicase up-frameshift 1 (UPF1) to reduce the half-life of SMD targets that form an SBS by either intramolecular or intermolecular base-pairing. Compared with STAU1, STAU2 binds ~10-fold more UPF1 and ~two- to fivefold more of those SBS-containing mRNAs that were tested, and it comparably promotes UPF1 helicase activity, which is critical for SMD. STAU1- or STAU2-mediated augmentation of UPF1 helicase activity is not accompanied by enhanced ATP hydrolysis but does depend on ATP binding and a basal level of UPF1 ATPase activity. Studies of STAU2 demonstrate it changes the conformation of RNA-bound UPF1. These findings, and evidence for STAU1-STAU1, STAU2-STAU2, and STAU1-STAU2 formation in vitro and in cells, are consistent with results from tethering assays: the decrease in mRNA abundance brought about by tethering siRNA-resistant STAU2 or STAU1 to an mRNA 3' UTR is inhibited by downregulating the abundance of cellular STAU2, STAU1, or UPF1. It follows that the efficiency of SMD in different cell types reflects the cumulative abundance of STAU1 and STAU2. We propose that STAU paralogs contribute to SMD by "greasing the wheels" of RNA-bound UPF1 so as to enhance its unwinding capacity per molecule of ATP hydrolyzed.
-
UPF1 association with the cap-binding protein, CBP80, promotes nonsense-mediated mRNA decay at two distinct steps.
Molecular cell, 2010Co-Authors: Jungwook Hwang, Yalan Tang, Hanae Sato, Daiki Matsuda, Lynne E. MaquatAbstract:Nonsense-mediated mRNA decay (NMD) is an mRNA surveillance mechanism that in mammals generally occurs upon recognition of a premature termination codon (PTC) during a pioneer round of translation. This round involves newly synthesized mRNA that is bound at its 5' end by the cap-binding protein (CBP) heterodimer CBP80-CBP20. Here we show that precluding the binding of the NMD factor UPF1 to CBP80 inhibits NMD at two steps: the association of SMG1 and UPF1 with the two eukaryotic release factors (eRFs) during SURF complex formation at a PTC, and the subsequent association of SMG1 and UPF1 with an exon-junction complex. We also demonstrate that UPF1 binds PTC-containing mRNA more efficiently than the corresponding PTC-free mRNA in a way that is promoted by the UPF1-CBP80 interaction. A unifying model proposes a choreographed series of protein-protein interactions occurring on an NMD target.
-
SMD and NMD are competitive pathways that contribute to myogenesis: Effects on PAX3 and myogenin mRNAs
Genes and Development, 2009Co-Authors: Chenguang Gong, Yoon Ki Kim, Collynn F. Woeller, Yalan Tang, Lynne E. MaquatAbstract:UPF1 functions in both Staufen 1 (STAU1)-mediated mRNA decay (SMD) and nonsense-mediated mRNA decay (NMD), which we show here are competitive pathways. STAU1- and UPF2-binding sites within UPF1 overlap so that STAU1 and UPF2 binding to UPF1 appear to be mutually exclusive. Furthermore, down-regulating the cellular abundance of STAU1, which inhibits SMD, increases the efficiency of NMD, whereas down-regulating the cellular abundance of UPF2, which inhibits NMD, increases the efficiency of SMD. Competition under physiological conditions is exemplified during the differentiation of C2C12 myoblasts to myotubes: The efficiency of SMD increases and the efficiency of NMD decreases, consistent with our finding that more STAU1 but less UPF2 bind UPF1 in myotubes compared with myoblasts. Moreover, an increase in the cellular level of UPF3X during myogenesis results in an increase in the efficiency of an alternative NMD pathway that, unlike classical NMD, is largely insensitive to UPF2 down-regulation. We discuss the remarkable balance between SMD and the two types of NMD in view of data indicating that PAX3 mRNA is an SMD target whose decay promotes myogenesis whereas myogenin mRNA is a classical NMD target encoding a protein required for myogenesis.
Fabien Bonneau - One of the best experts on this subject based on the ideXlab platform.
-
structure of substrate bound smg1 8 9 kinase complex reveals molecular basis for phosphorylation specificity
eLife, 2020Co-Authors: Lukas M Langer, Fabien Bonneau, Yair Gat, Elena ContiAbstract:PI3K-related kinases (PIKKs) are large Serine/Threonine (Ser/Thr)-protein kinases central to the regulation of many fundamental cellular processes. PIKK family member SMG1 orchestrates progression of an RNA quality control pathway, termed nonsense-mediated mRNA decay (NMD), by phosphorylating the NMD factor UPF1. Phosphorylation of UPF1 occurs in its unstructured N- and C-terminal regions at Serine/Threonine-Glutamine (SQ) motifs. How SMG1 and other PIKKs specifically recognize SQ motifs has remained unclear. Here, we present a cryo-electron microscopy (cryo-EM) reconstruction of a human SMG1-8-9 kinase complex bound to a UPF1 phosphorylation site at an overall resolution of 2.9 A. This structure provides the first snapshot of a human PIKK with a substrate-bound active site. Together with biochemical assays, it rationalizes how SMG1 and perhaps other PIKKs specifically phosphorylate Ser/Thr-containing motifs with a glutamine residue at position +1 and a hydrophobic residue at position -1, thus elucidating the molecular basis for phosphorylation site recognition.
-
A conserved structural element in the RNA helicase UPF1 regulates its catalytic activity in an isoform-specific manner
Nucleic Acids Research, 2018Co-Authors: Manjeera Gowravaram, Hervé Le Hir, Fabien Bonneau, Francesca Fiorini, Joanne Kanaan, Vincent Croquette, Vincent Maciej, Saurabh Raj, Sutapa ChakrabartiAbstract:The RNA helicase UPF1 is a key component of the nonsense mediated mRNA decay (NMD) pathway. Previous X-ray crystal structures of UPF1 elucidated the molecular mechanisms of its catalytic activity and regulation. In this study, we examine features of the UPF1 core and identify a structural element that adopts different conformations in the various nucleotide-and RNA-bound states of UPF1. We demonstrate, using biochemical and single molecule assays, that this structural element modulates UPF1 catalytic activity and thereby refer to it as the regulatory loop. Interestingly, there are two alternatively spliced isoforms of UPF1 in mammals which differ only in the lengths of their regulatory loops. The loop in isoform 1 (UPF1 1) is 11 residues longer than that of isoform 2. We find that this small insertion in UPF1 1 leads to a twofold increase in its translocation and ATPase activities. To determine the mechanistic basis of this differential catalytic activity, we have determined the X-ray crystal structure of the helicase core of UPF1 1 in its apo-state. Our results point toward a novel mechanism of regulation of RNA helicases, wherein alternative splicing leads to subtle structural rearrangements within the protein that are critical to modulate enzyme movements and catalytic activity.
-
molecular mechanisms for the rna dependent atpase activity of UPF1 and its regulation by upf2
Molecular Cell, 2011Co-Authors: Sutapa Chakrabarti, Hervé Le Hir, Fabien Bonneau, Francesca Fiorini, Uma Jayachandran, Claire Basquin, Silvia Domcke, Elena ContiAbstract:Summary UPF1 is a crucial factor in nonsense-mediated mRNA decay, the eukaryotic surveillance pathway that degrades mRNAs containing premature stop codons. The essential RNA-dependent ATPase activity of UPF1 is triggered by the formation of the surveillance complex with Upf2-Upf3. We report crystal structures of UPF1 in the presence and absence of the CH domain, captured in the transition state with ADP:AlF 4 − and RNA. In isolation, UPF1 clamps onto the RNA, enclosing it in a channel formed by both the catalytic and regulatory domains. Upon binding to Upf2, the regulatory CH domain of UPF1 undergoes a large conformational change, causing the catalytic helicase domain to bind RNA less extensively and triggering its helicase activity. Formation of the surveillance complex thus modifies the RNA binding properties and the catalytic activity of UPF1, causing it to switch from an RNA-clamping mode to an RNA-unwinding mode.
-
nmd factors upf2 and upf3 bridge UPF1 to the exon junction complex and stimulate its rna helicase activity
Nature Structural & Molecular Biology, 2008Co-Authors: Hala Chamieh, Lionel Ballut, Fabien BonneauAbstract:NMD factors UPF2 and UPF3 bridge UPF1 to the exon junction complex and stimulate its RNA helicase activity
-
nmd factors upf2 and upf3 bridge UPF1 to the exon junction complex and stimulate its rna helicase activity
Nature Structural & Molecular Biology, 2008Co-Authors: Hala Chamieh, Lionel Ballut, Fabien Bonneau, Hervé Le HirAbstract:Nonsense-mediated mRNA decay (NMD) eliminates mRNAs containing a premature translation termination codon through the recruitment of the conserved NMD factors UPF1, UPF2 and UPF3. In humans, a dynamic assembly pathway allows UPF1 to join UPF2 and UPF3 recruited to the mRNA by the exon-junction complex (EJC). Here we show that the recombinant EJC core is sufficient to reconstitute, with the three UPF proteins, a stable heptameric complex on RNA. The EJC proteins MAGOH, Y14 and eIF4AIII provide a composite binding site for UPF3b that serves as a bridge to UPF2 and UPF1. In the UPF trimeric complex, UPF2 and UPF3b cooperatively stimulate both ATPase and RNA helicase activities of UPF1. This work demonstrates that the EJC core is sufficient to stably anchor the UPF proteins to mRNA and provides insights into the regulation of its central effector, UPF1.
Priya S Shah - One of the best experts on this subject based on the ideXlab platform.
-
the cellular nmd pathway restricts zika virus infection and is targeted by the viral capsid protein
Mbio, 2018Co-Authors: Krystal A Fontaine, Kristoffer E Leon, Mir M Khalid, Sakshi Tomar, David Jimenezmorales, Mariah Dunlap, Julia A Kaye, Priya S ShahAbstract:Zika virus (ZIKV) infection of neural progenitor cells (NPCs) in utero is associated with neurological disorders, such as microcephaly, but a detailed molecular understanding of ZIKV-induced pathogenesis is lacking. Here we show that in vitro ZIKV infection of human cells, including NPCs, causes disruption of the nonsense-mediated mRNA decay (NMD) pathway. NMD is a cellular mRNA surveillance mechanism that is required for normal brain size in mice. Using affinity purification-mass spectrometry, we identified multiple cellular NMD factors that bind to the viral capsid protein, including the central NMD regulator up-frameshift protein 1 (UPF1). Endogenous UPF1 interacted with the ZIKV capsid protein in coimmunoprecipitation experiments, and capsid expression posttranscriptionally downregulated UPF1 protein levels, a process that we confirmed occurs during ZIKV infection. Cellular fractionation studies show that the ZIKV capsid protein specifically targets nuclear UPF1 for degradation via the proteasome. A further decrease in UPF1 levels by RNAi significantly enhanced ZIKV infection in NPC cultures, consistent with a model in which NMD restricts ZIKV infection in the fetal brain. We propose that ZIKV, via the capsid protein, has evolved a strategy to lower UPF1 levels and dampen antiviral activities of NMD, which in turn contributes to neuropathology in vivo IMPORTANCE Zika virus (ZIKV) is a significant global health threat, as infection has been linked to serious neurological complications, including microcephaly. Using a human stem cell-derived neural progenitor model system, we find that a critical cellular quality control process called the nonsense-mediated mRNA decay (NMD) pathway is disrupted during ZIKV infection. Importantly, disruption of the NMD pathway is a known cause of microcephaly and other neurological disorders. We further identify an interaction between the capsid protein of ZIKV and up-frameshift protein 1 (UPF1), the master regulator of NMD, and show that ZIKV capsid targets UPF1 for degradation. Together, these results offer a new mechanism for how ZIKV infection can cause neuropathology in the developing brain.
-
the cellular nmd pathway restricts zika virus infection and is targeted by the viral capsid protein
bioRxiv, 2018Co-Authors: Krystal A Fontaine, Kristoffer E Leon, Mir M Khalid, David Jimenezmorales, Julia A Kaye, Priya S Shah, Steven Finkbeiner, Nevan J Krogan, Melanie OttAbstract:Zika virus (ZIKV) infection of neural progenitor cells (NPCs) in utero is associated with neurological disorders, such as microcephaly1, but a detailed molecular understanding of ZIKV-induced pathogenesis is lacking. Here we show that in vitro ZIKV infection of human cells, including NPCs, causes disruption of the nonsense-mediated mRNA decay (NMD) pathway. NMD is a cellular mRNA surveillance mechanism that is required for normal brain size in mice2-4. Using affinity purification-mass spectrometry, we identified multiple cellular NMD factors that bind to the viral capsid protein, including the central NMD regulator up-frameshift protein 1 (UPF1)5. Endogenous UPF1 interacted with the viral capsid protein in co-immunoprecipitation experiments and capsid expression post-transcriptionally downregulated UPF1, a process that we confirmed occurs during de novo ZIKV infection. A further decrease in UPF1 levels by RNAi significantly enhanced ZIKV infection in NPC cultures. We therefore propose that ZIKV, via the capsid protein, has evolved a strategy to dampen antiviral activities of NMD6,7, which subsequently contributes to neuropathology in vivo.
Kristoffer E Leon - One of the best experts on this subject based on the ideXlab platform.
-
the cellular nmd pathway restricts zika virus infection and is targeted by the viral capsid protein
Mbio, 2018Co-Authors: Krystal A Fontaine, Kristoffer E Leon, Mir M Khalid, Sakshi Tomar, David Jimenezmorales, Mariah Dunlap, Julia A Kaye, Priya S ShahAbstract:Zika virus (ZIKV) infection of neural progenitor cells (NPCs) in utero is associated with neurological disorders, such as microcephaly, but a detailed molecular understanding of ZIKV-induced pathogenesis is lacking. Here we show that in vitro ZIKV infection of human cells, including NPCs, causes disruption of the nonsense-mediated mRNA decay (NMD) pathway. NMD is a cellular mRNA surveillance mechanism that is required for normal brain size in mice. Using affinity purification-mass spectrometry, we identified multiple cellular NMD factors that bind to the viral capsid protein, including the central NMD regulator up-frameshift protein 1 (UPF1). Endogenous UPF1 interacted with the ZIKV capsid protein in coimmunoprecipitation experiments, and capsid expression posttranscriptionally downregulated UPF1 protein levels, a process that we confirmed occurs during ZIKV infection. Cellular fractionation studies show that the ZIKV capsid protein specifically targets nuclear UPF1 for degradation via the proteasome. A further decrease in UPF1 levels by RNAi significantly enhanced ZIKV infection in NPC cultures, consistent with a model in which NMD restricts ZIKV infection in the fetal brain. We propose that ZIKV, via the capsid protein, has evolved a strategy to lower UPF1 levels and dampen antiviral activities of NMD, which in turn contributes to neuropathology in vivo IMPORTANCE Zika virus (ZIKV) is a significant global health threat, as infection has been linked to serious neurological complications, including microcephaly. Using a human stem cell-derived neural progenitor model system, we find that a critical cellular quality control process called the nonsense-mediated mRNA decay (NMD) pathway is disrupted during ZIKV infection. Importantly, disruption of the NMD pathway is a known cause of microcephaly and other neurological disorders. We further identify an interaction between the capsid protein of ZIKV and up-frameshift protein 1 (UPF1), the master regulator of NMD, and show that ZIKV capsid targets UPF1 for degradation. Together, these results offer a new mechanism for how ZIKV infection can cause neuropathology in the developing brain.
-
the cellular nmd pathway restricts zika virus infection and is targeted by the viral capsid protein
bioRxiv, 2018Co-Authors: Krystal A Fontaine, Kristoffer E Leon, Mir M Khalid, David Jimenezmorales, Julia A Kaye, Priya S Shah, Steven Finkbeiner, Nevan J Krogan, Melanie OttAbstract:Zika virus (ZIKV) infection of neural progenitor cells (NPCs) in utero is associated with neurological disorders, such as microcephaly1, but a detailed molecular understanding of ZIKV-induced pathogenesis is lacking. Here we show that in vitro ZIKV infection of human cells, including NPCs, causes disruption of the nonsense-mediated mRNA decay (NMD) pathway. NMD is a cellular mRNA surveillance mechanism that is required for normal brain size in mice2-4. Using affinity purification-mass spectrometry, we identified multiple cellular NMD factors that bind to the viral capsid protein, including the central NMD regulator up-frameshift protein 1 (UPF1)5. Endogenous UPF1 interacted with the viral capsid protein in co-immunoprecipitation experiments and capsid expression post-transcriptionally downregulated UPF1, a process that we confirmed occurs during de novo ZIKV infection. A further decrease in UPF1 levels by RNAi significantly enhanced ZIKV infection in NPC cultures. We therefore propose that ZIKV, via the capsid protein, has evolved a strategy to dampen antiviral activities of NMD6,7, which subsequently contributes to neuropathology in vivo.
