Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a human motor neuron degenerative disease caused by loss-of-function mutations of the immunoglobulin u-binding protein 2 (IGHMBP2), a putative RNA/DNA helicase. The co-investigator Cox previously identified the mouse Ighmbp2 gene as the causative gene of the mouse neuromuscular degeneration (nmd) phenotype by a positional cloning approach. We have also identified a major genetic modifier of its phenotypic expression (Mnm). The function of IGHMBP2 and its role in the motor neuron degeneration that underlies the pathogenesis of SMARD1 are unknown. We propose to investigate the function of IGHMBP2 and to uncover the molecular defect(s) responsible for motor neuron degeneration caused by reduced IGHMBP2 levels, by implementing an inter-disciplinary and inter-institutional collaborative approach that will allow us to combine state of the art biochemical and genetic investigations. Toward this goal, we have isolated IGHMBP2 interacting proteins and small RNAs that associate with this helicase and we have employed powerful genetic approaches to identify the critical cell-types that require nmd gene activity using tissue-specific transgenic rescue. Our ability to manipulate the severity of the disease phenotype genetically with at least one modifier gene suggests that a molecular pathway exists with the potential for genetic or clinical intervention. Thus, the nmd mouse and the Mnm modifier gene provide a unique opportunity to identify the underlying processes of neurodegeneration and provide possible entry points in which to intervene in the disease pathway. Our genetic studies will be complemented by biochemical studies aimed towards characterization of the function of IGHMBP2 in cellular and mouse models of SMARD1 and we will extend our studies in human tissues from SMARD1 patients. These studies will likely uncover an entirely novel pathway of RNA regulation and will advance significantly our understanding of RNA processing in motor neurons and the contribution of RNA dysregulation in motor neuron degeneration.We propose to investigate the pathobiology of an inherited, human neurodegenerative disease. Our studies will shed light on pathogenetic mechanisms of human motor neuron diseases and promote the design of strategies to combat these lethal diseases.
| Vourekas, Anastassios; Mourelatos, Zissimos (2014) HITS-CLIP (CLIP-Seq) for mouse Piwi proteins. Methods Mol Biol 1093:73-95 |
| Ibrahim, Fadia; Maragkakis, Manolis; Alexiou, Panagiotis et al. (2013) Identification of in vivo, conserved, TAF15 RNA binding sites reveals the impact of TAF15 on the neuronal transcriptome. Cell Rep 3:301-8 |
| Nakaya, Tadashi; Alexiou, Panagiotis; Maragkakis, Manolis et al. (2013) FUS regulates genes coding for RNA-binding proteins in neurons by binding to their highly conserved introns. RNA 19:498-509 |
| Couthouis, Julien; Hart, Michael P; Erion, Renske et al. (2012) Evaluating the role of the FUS/TLS-related gene EWSR1 in amyotrophic lateral sclerosis. Hum Mol Genet 21:2899-911 |
| Ibrahim, Fadia; Nakaya, Tadashi; Mourelatos, Zissimos (2012) RNA dysregulation in diseases of motor neurons. Annu Rev Pathol 7:323-52 |
| Couthouis, Julien; Hart, Michael P; Shorter, James et al. (2011) A yeast functional screen predicts new candidate ALS disease genes. Proc Natl Acad Sci U S A 108:20881-90 |
| Kirino, Yohei; Vourekas, Anastassios; Khandros, Eugene et al. (2011) Immunoprecipitation of piRNPs and directional, next generation sequencing of piRNAs. Methods Mol Biol 725:281-93 |
| Kirino, Yohei; Vourekas, Anastassios; Sayed, Nabil et al. (2010) Arginine methylation of Aubergine mediates Tudor binding and germ plasm localization. RNA 16:70-8 |
| de Planell-Saguer, Mariangels; Rodicio, Maria Celina; Mourelatos, Zissimos (2010) Rapid in situ codetection of noncoding RNAs and proteins in cells and formalin-fixed paraffin-embedded tissue sections without protease treatment. Nat Protoc 5:1061-73 |
| Kirino, Yohei; Vourekas, Anastassios; Kim, Namwoo et al. (2010) Arginine methylation of vasa protein is conserved across phyla. J Biol Chem 285:8148-54 |
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