Search

Your search keyword '"Monani, Umrao R."' showing total 150 results
Start Over Author "Monani, Umrao R."
150 results on '"Monani, Umrao R."'

1. Muscle-specific SMN reduction reveals motor neuron-independent disease in spinal muscular atrophy models

Author

Kim, Jeong-Ki, Jha, Narendra N., Feng, Zhihua, Faleiro, Michelle R., Chiriboga, Claudia A., Wei-Lapierre, Lan, Dirksen, Robert T., Ko, Chien-Ping, and Monani, Umrao R.

Subjects
Spinal muscular atrophy, Skeletal muscle, Medical research, Drug approval, Neurons, Muscular atrophy, Paralysis, Animal genetic engineering, Diseases, Health care industry, The Jackson Laboratory, Spinraza (Medication)
Abstract

Paucity of the survival motor neuron (SMN) protein triggers the oft-fatal infantile-onset motor neuron disorder, spinal muscular atrophy (SMA). Augmenting the protein is one means of treating SMA and recently led to FDA approval of an intrathecally delivered SMN-enhancing oligonucleotide currently in use. Notwithstanding the advent of this and other therapies for SMA, it is unclear whether the paralysis associated with the disease derives solely from dysfunctional motor neurons that may be efficiently targeted by restricted delivery of SMN-enhancing agents to the nervous system, or stems from broader defects of the motor unit, arguing for systemic SMN repletion. We investigated the disease-contributing effects of low SMN in one relevant peripheral organ--skeletal muscle--by selectively depleting the protein in only this tissue. We found that muscle deprived of SMN was profoundly damaged. Although a disease phenotype was not immediately obvious, persistent low levels of the protein eventually resulted in muscle fiber defects, neuromuscular junction abnormalities, compromised motor performance, and premature death. Importantly, restoring SMN after the onset of muscle pathology reversed disease. Our results provide the most compelling evidence yet for a direct contributing role of muscle in SMA and argue that an optimal therapy for the disease must be designed to treat this aspect of the dysfunctional motor unit., Introduction Homozygous mutations in the survival of motor neuron 1 (SMN1) gene result in reduced levels of the SMN protein and trigger the infantile-onset neuromuscular disease, spinal muscular atrophy (SMA) [...]

Published
2020
Full Text
View/download PDF

2. SMN regulates axonal local translation via miR-183/mTOR pathway

Author

Kye, Min Jeong, Niederst, Emily D, Wertz, Mary H, do Carmo G. Gonçalves, Inês, Akten, Bikem, Dover, Katarzyna Z, Peters, Miriam, Riessland, Markus, Neveu, Pierre, Wirth, Brunhilde, Kosik, Kenneth S, Sardi, S Pablo, Monani, Umrao R, Passini, Marco A, and Sahin, Mustafa

Subjects
Rare Diseases, Genetics, Neurodegenerative, Pediatric, Spinal Muscular Atrophy, Neurosciences, 2.1 Biological and endogenous factors, Aetiology, Neurological, Good Health and Well Being, 3' Untranslated Regions, Animals, Axons, MicroRNAs, Muscular Atrophy, Spinal, Neurons, Primary Cell Culture, Protein Biosynthesis, RNA, Messenger, Rats, Sprague-Dawley, Survival of Motor Neuron 1 Protein, TOR Serine-Threonine Kinases, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Reduced expression of SMN protein causes spinal muscular atrophy (SMA), a neurodegenerative disorder leading to motor neuron dysfunction and loss. However, the molecular mechanisms by which SMN regulates neuronal dysfunction are not fully understood. Here, we report that reduced SMN protein level alters miRNA expression and distribution in neurons. In particular, miR-183 levels are increased in neurites of SMN-deficient neurons. We demonstrate that miR-183 regulates translation of mTor via direct binding to its 3' UTR. Interestingly, local axonal translation of mTor is reduced in SMN-deficient neurons, and this can be recovered by miR-183 inhibition. Finally, inhibition of miR-183 expression in the spinal cord of an SMA mouse model prolongs survival and improves motor function of Smn-mutant mice. Together, these observations suggest that axonal miRNAs and the mTOR pathway are previously unidentified molecular mechanisms contributing to SMA pathology.

Published
2014

7. A spinal muscular atrophy modifier implicates the SMN protein in SNARE complex assembly at neuromuscular synapses

Author

Kim, Jeong-Ki, primary, Jha, Narendra N., additional, Awano, Tomoyuki, additional, Caine, Charlotte, additional, Gollapalli, Kishore, additional, Welby, Emily, additional, Kim, Seung-Soo, additional, Fuentes-Moliz, Andrea, additional, Wang, Xueyong, additional, Feng, Zhihua, additional, Sera, Fusako, additional, Takeda, Taishi, additional, Homma, Shunichi, additional, Ko, Chien-Ping, additional, Tabares, Lucia, additional, Ebert, Allison D., additional, Rich, Mark M., additional, and Monani, Umrao R., additional

Published
2023
Full Text
View/download PDF

9. Contributors

Author

Aaen, Gregory S., primary, Abend, Nicholas Scott, additional, Abou-Hamden, Amal, additional, Allen, Jeffrey C., additional, Amato, Anthony A., additional, Amlie-Lefond, Catherine, additional, Ashwal, Stephen, additional, Bailey, Russell C., additional, Bale, James F., additional, Banwell, Brenda, additional, Barañano, Kristin W., additional, Barkovich, A. James, additional, Barohn, Richard J., additional, Bartels, Ute K., additional, Bartnik-Olson, Brenda, additional, Barzilai, Ori, additional, Bassuk, Alexander, additional, Bearden, David R., additional, Ben-Sira, Liat, additional, Bernard, Timothy J., additional, Berry-Kravis, Elizabeth, additional, Beslow, Lauren A., additional, Biegel, Jaclyn A., additional, Billinghurst, Lori, additional, Birnbaum, Angela K., additional, Blackburn, Joanna S., additional, Bobowski, Nuala, additional, Boire, Adrienne, additional, Bönnemann, Carsten G., additional, Bonifacio, Sonia L., additional, Bonthius, Daniel J., additional, Borcherding, Breck, additional, Branchford, Brian R., additional, Brandsema, John, additional, Brennan, Kathryn M., additional, Brenton, J. Nicholas, additional, Brooks-Kayal, Amy R., additional, Brown, Lawrence W., additional, Buchalter, Jeffrey, additional, Camfield, Carol S., additional, Camfield, Peter R., additional, Campoy, Cristina, additional, Carpenter, Jessica L., additional, Chang, Taeun, additional, Chau, Vann, additional, Chi, Susan N., additional, Chiriboga, Claudia A., additional, Cho, Yoon-Jae, additional, Christian, Cindy W., additional, Chrestian, Nicholas, additional, Cilio, Maria Roberta, additional, Clark, Robin D., additional, Cohen, Bruce H., additional, Cohn, Ronald D., additional, Connolly, Anne M., additional, Constable, Todd, additional, Constantini, Shlomi, additional, Conway, Jeannine M., additional, Coulter, David L., additional, Cowan, Tina M., additional, Dale, Russell C., additional, Darbro, Benjamin, additional, Darras, Basil T., additional, Dastgir, Jahannaz, additional, De Meirleir, Linda, additional, De Vivo, Darryl C., additional, de Vries, Linda S., additional, Deisch, Jeremy K., additional, Deltenre, Paul, additional, Desai, Jay, additional, Descartes, Maria, additional, deVeber, Gabrielle, additional, Dhamne, Sameer C., additional, Diaz, Jullianne, additional, DiMauro, Salvatore, additional, Dobyns, William B., additional, Doherty, Dan, additional, Donner, Elizabeth J., additional, Dosenbach, Nico U.F., additional, Dowling, James J., additional, Drake, James M., additional, Ejerskov, Cecile, additional, Engel, Andrew G., additional, Enns, Gregory M., additional, Escolano-Margarit, María Victoria, additional, Etzion, Iris, additional, Fatemi, S. Ali, additional, Fehlings, Darcy L., additional, Feinberg, Michelle Lauren, additional, Ferriero, Donna M., additional, Filipek, Pauline A., additional, Finkel, Richard S., additional, Fisher, Paul G., additional, Flanigan, Kevin, additional, Foreman, Nicholas K., additional, Franco, Israel, additional, Frank, Yitzchak, additional, Fredrick, Douglas R., additional, Freeze, Hudson H., additional, Fuente-Mora, Cristina, additional, Furman, Joseph M., additional, Gallagher, Renata C., additional, Garel, Catherine, additional, Gertsch, Emily, additional, Gilbert, Donald L., additional, Gilles, Elizabeth E., additional, Giza, Christopher C., additional, Glaser, Carol A., additional, Glass, Hannah C., additional, Glauser, Tracy, additional, Glykys, Joseph, additional, Goldstein, Amy, additional, Gonorazky, Hernan Dario, additional, Gonzalez, Rodolfo, additional, Goodkin, Howard P., additional, Graham, John M., additional, Greninger, Alexander L., additional, Gronseth, Gary, additional, Gropman, Andrea L., additional, Grundy, Richard, additional, Guerrini, Renzo, additional, Gupta, Nalin, additional, Hahn, Jin S., additional, Hamblin, Milton H., additional, Hani, Abeer J., additional, Hanmantgad, Sharyu, additional, Harbert, Mary J., additional, Harini, Chellamani, additional, Harriott, Andrea M., additional, Heatwole, Chad, additional, Hershey, Andrew D., additional, Hirtz, Deborah G., additional, Holmes, Gregory L., additional, Holshouser, Barbara A., additional, Hurwitz, Kathleen A., additional, Hwang, Eugene, additional, Ichord, Rebecca N., additional, Jafar-Nejad, Paymaan, additional, Jain, Sejal V., additional, Jordan, Lori, additional, Kabbouche, Marielle A., additional, Kacperski, Joanne, additional, Kang, Peter B., additional, Kariannis, Matthias A., additional, Kaufmann, Horacio, additional, Kaye, Harper L., additional, Keating, Robert, additional, Kennedy, Colin R., additional, Khakoo, Yasmin, additional, Kirton, Adam, additional, Kissel, John T., additional, Knupp, Kelly G., additional, Korf, Bruce R., additional, Kossoff, Eric H., additional, Kothare, Sanjeev V., additional, Kupfer, Oren, additional, LaFrance, W. Curt, additional, Latal, Beatrice, additional, Leber, Steven M., additional, Lee, Jean-Pyo, additional, Leppik, Ilo E., additional, Lerman-Sagie, Tally, additional, Lerner, Jason T., additional, Leventer, Richard J., additional, Licht, Daniel J., additional, Lichter-Konecki, Uta, additional, Lidar, Zvi, additional, Liem, Djin Gie, additional, Loddenkemper, Tobias, additional, Long, Roger K., additional, Luc, Quyen N., additional, Mackay, Mark, additional, Majnemer, Annette, additional, Makhani, Naila, additional, Malinger, Gustavo, additional, Mandelbaum, David E., additional, Maricich, Stephen M., additional, Maski, Kiran P., additional, Mathur, Mudit, additional, Matthews, Dennis J., additional, McMahon, Kelly, additional, DeMara-Hoth, Megan B., additional, Mendelsohn, Bryce, additional, Mennella, Julie A., additional, Ment, Laura R., additional, Mercuri, Eugenio, additional, Michelson, David J., additional, Mikati, Mohamad A., additional, Mikhail, Fady M., additional, Miller, Steven Paul, additional, Milunsky, Jeff M., additional, Mink, Jonathan W., additional, Mirzaa, Ghayda M., additional, Mitchell, Wendy G., additional, Mohan, Michael A., additional, Mohassel, Payam, additional, Moharir, Mahendranath, additional, Monani, Umrao R., additional, Monje Deisseroth, Michelle, additional, Moodley, Manikum, additional, Mower, Andrew, additional, Moxley, Richard T., additional, Mueller, Sabine, additional, Muotri, Alysson R., additional, Nagamani, Sandesh C.S., additional, Narayanan, Mohan J., additional, Narayanan, Vinodh, additional, Nass, Ruth D., additional, Neul, Jeffrey L., additional, Nevo, Yoram, additional, Ng, Bobby G., additional, Nickels, Katherine C., additional, Nimmo, Graeme A.M., additional, Noetzel, Michael J., additional, Norcliffe-Kaufmann, Lucy, additional, Nordli, Douglas R., additional, Nowak-Göttl, Ulrike, additional, O'Brien, Hope L., additional, Oleszek, Joyce, additional, Oskoui, Maryam, additional, Paciorkowski, Alex R., additional, Packer, Roger J., additional, Packman, Seymour, additional, Palma, Jose-Alberto, additional, Pardo, Andrea C., additional, Parsons, Julie A., additional, Partridge, John Colin, additional, Pastores, Gregory M., additional, Patterson, Marc C., additional, Pearce, William J., additional, Pearl, Phillip L., additional, Penner, Melanie, additional, Percival, Leila, additional, Pereira, Marcia, additional, Pfister, Stefan M., additional, Phillips, John, additional, Plecko, Barbara, additional, Plioplys, Sigita, additional, Poduri, Annapurna, additional, Poisson, Sharon, additional, Pomeroy, Scott L., additional, Poretti, Andrea, additional, Powers, Scott W., additional, Pranzatelli, Michael R., additional, Przekop, Allison, additional, Rabie, Malcolm, additional, Rangasamy, Sampathkumar, additional, Raymond, Gerald V., additional, Reddy, Alyssa T., additional, Rendleman, Rebecca L., additional, Rho, Jong M., additional, Rodan, Lance H., additional, Roddy, Sarah M., additional, Rogers, Elizabeth E., additional, Rosenthal, Stephen M., additional, Rosman, N. Paul, additional, Ross, M. Elizabeth, additional, Rotenberg, Alexander, additional, Rust, Robert S., additional, Sanchez, Cheryl P., additional, Sanchez, Pedro, additional, Sánchez Fernández, Iván, additional, Sands, Tristan T., additional, Sanger, Terence D., additional, Sannagowdara, Kumar, additional, Scheinost, Dustin, additional, Scher, Mark S., additional, Schor, Nina F., additional, Schrauwen, Isabelle, additional, Segal, Michael M., additional, Seinfeld, Syndi, additional, Selcen, Duygu, additional, Seltzer, Laurie E., additional, Semrud-Clikeman, Margaret, additional, Shaw, Dennis W., additional, Shaywitz, Bennett A., additional, Shaywitz, Sally E., additional, Shellhaas, Renée A., additional, Sherr, Elliott H., additional, Sheth, Rita D., additional, Shevell, Michael I., additional, Shinnar, Shlomo, additional, Shofty, Ben, additional, Shu, Stanford K., additional, Shy, Michael E., additional, Silveira Moriyama, Laura, additional, Silvestri, Nicholas J., additional, Sims, Katherine B., additional, Singer, Harvey S., additional, Singhal, Nilika Shah, additional, Smith, Craig M., additional, Smith, Edward, additional, Smith, Stephen A., additional, Snyder, Evan Y., additional, Soul, Janet, additional, Spalink, Christy L., additional, Spencer, Karen A., additional, Stafstrom, Carl E., additional, Steinfeld, Robert, additional, Strober, Jonathan B., additional, Sullivan, Joseph, additional, Swaiman, Kenneth F., additional, Swoboda, Kathryn J., additional, Tate, Elizabeth D., additional, Tatum, William O., additional, Tein, Ingrid, additional, Tekulve, Kristyn, additional, Tenney, Jeffrey R., additional, Thiele, Elizabeth A., additional, Thompson-Stone, Robert, additional, Tochen, Laura, additional, Tormoehlen, Laura M., additional, Tran, Lily, additional, Trauner, Doris A., additional, Turnacioglu, Sinan O., additional, Ullrich, Nicole J., additional, Urion, David K., additional, Van Camp, Guy, additional, Van Hirtum-Das, Michèle, additional, van Karnebeek, Clara D.M., additional, Van Maldergem, Lionel, additional, Vanderver, Adeline, additional, Vitanza, Nicholas A., additional, von Rhein, Michael, additional, von Scheven, Emily, additional, Wagner, Ann, additional, Wainwright, Mark S., additional, Walker, Melissa A., additional, Walkup, John T., additional, Walsh, Laurence, additional, Walters-Sen, Lauren C., additional, Wang, Raymond Y., additional, Warner, Thomas T., additional, Whelan, Harry T., additional, Weinberg, Geoffrey A., additional, Wells, Elizabeth M., additional, Wheless, James W., additional, Wirrell, Elaine C., additional, Wisoff, Jeffrey H., additional, Wolf, Nicole I., additional, Wolfe, Gil I., additional, Wright, F. Virginia, additional, Wycliffe, Nathaniel D., additional, Yang, Michele L., additional, Yuskaitis, Christopher J., additional, Zoghbi, Huda Y., additional, and Zupanc, Mary L., additional

Published
2017
Full Text
View/download PDF

13. Requirement of enhanced survival motoneuron protein imposed during neuromuscular junction maturation

Author

Kariya, Shingo, Obis, Teresa, Garone, Caterina, Akay, Turgay, Sera, Fusako, Iwata, Shinichi, Homma, Shunichi, and Monani, Umrao R.

Subjects
Motor neurons -- Physiological aspects -- Research, Neuromuscular junction -- Research, Spinal muscular atrophy -- Development and progression -- Care and treatment -- Research, Health care industry
Abstract

Spinal muscular atrophy is a common motor neuron disease caused by low survival motoneuron (SMN), a key protein in the proper splicing of genes. Restoring the protein is therefore a promising therapeutic strategy. Implementation of this strategy, however, depends on defining the temporal requirements for SMN. Here, we used controlled knockdown of SMN in transgenic mice to determine the precise postnatal stage requirements for this protein. Reducing SMN in neonatal mice resulted in a classic SMA-like phenotype. Unexpectedly, depletion of SMN in adults had relatively little effect. Insensitivity to low SMN emerged abruptly at postnatal day 17, which coincided with establishment of the fully mature neuromuscular junction (NMJ). Mature animals depleted of SMN eventually exhibited evidence of selective neuromuscular pathology that was made worse by traumatic injury. The ability to regenerate the mature NMJ in aged or injured SMN-depleted mice was grossly impaired, a likely consequence of the inability to meet the surge in demand for motoneuronal SMN that was seen in controls. Our results demonstrate that relative maturity of the NMJ determines the temporal requirement for the SMN protein. These observations suggest that the use of potent but potentially deleterious SMN-enhancing agents could be tapered in human patients once the neuromuscular system matures and reintroduced as needed to enhance SMN for remodeling aged or injured NMJs., Introduction Lesions in the survival of motor neuron 1 (SMN1) gene underlie the common and often fatal pediatric neuromuscular disorder spinal muscular atrophy (SMA) (1). The disease, defined primarily by [...]

Published
2014
Full Text
View/download PDF

14. List of Contributors

Author

Akman, Hasan O., primary, Axelrod, Felicia B., additional, Baets, Jonathan, additional, Beggs, Alan H., additional, Bönnemann, Carsten G., additional, Brennan, Kathryn M., additional, Brown, Robert H., additional, Bushby, Kate, additional, Carpenter, Stirling, additional, Chung, Wendy, additional, Ciafaloni, Emma, additional, Ciarlini, Pedro D.S.C., additional, Crawford, Thomas O., additional, Darras, Basil T., additional, David, William S., additional, De Girolami, Umberto, additional, De Vivo, Darryl C., additional, Deymeer, Feza, additional, DiMauro, Salvatore, additional, Dowling, James J., additional, Durmus, Hacer, additional, Engel, Andrew G., additional, Engle, Elizabeth C., additional, Goebel, Hans H., additional, Grattan-Smith, Padraic J., additional, Guglieri, Michela, additional, Guntrum, Debra, additional, Hall, Judith G., additional, Hinton, Veronica, additional, Iannaccone, Susan T., additional, Jones, H. Royden, additional, Jurkat-Rott, Karin, additional, Kang, Peter B., additional, Kaufmann, Horacio, additional, Kaufmann, Petra, additional, Klingler, Werner, additional, Kunkel, Louis M., additional, Lehmann-Horn, Frank, additional, Levin, Kerry H., additional, Liew, Wendy K.M., additional, Logan, Deirdre, additional, Maricich, Stephen M., additional, Markowitz, Jennifer A., additional, Marques, Wilson, additional, Mason, Thornton B.A., additional, McKeon, Andrew, additional, McMillan, Hugh J., additional, Menache-Starobinski, Caroline C., additional, Mendell, Jerry R., additional, Mercuri, Eugenio, additional, Mohassel, Payam, additional, Monani, Umrao R., additional, Montes, Jacqueline, additional, Moodley, Manikum, additional, Moxley, Richard T., additional, Muntoni, Francesco, additional, North, Kathryn N., additional, Oldfors, Anders, additional, Oskoui, Maryam, additional, Ouvrier, Robert A., additional, Pachman, Lauren M., additional, Pandolfo, Massimo, additional, Paradas, Carmen, additional, Patterson, Marc C., additional, Percy, Alan K., additional, Pitt, Matthew, additional, Pleasure, David, additional, Quijano-Roy, Susana, additional, Renault, Francis, additional, Rodino-Klapac, Louise R., additional, Roig-Quilis, Manuel, additional, Roye, David P., additional, Rüdel, Reinhardt, additional, Russman, Barry S., additional, Ryan, Monique M., additional, Sakonju, Ai, additional, Sarnat, Harvey B., additional, Scott, William A., additional, Seay, Alan R., additional, Serdaroglu-Oflazer, Piraye, additional, Sethna, Navil F., additional, Sheha, Evan D., additional, Shy, Michael E., additional, Sreedharan, Jemeen, additional, Strauss, Nancy E., additional, Tawil, Rabi, additional, Tein, Ingrid, additional, Tracy, Jennifer A., additional, Udd, Bjarne, additional, van der Maarel, Silvère M., additional, Vincent, Angela, additional, Volpe, Joseph J., additional, Wilmshurst, Jo M., additional, Xu, Nanfang, additional, Yiu, Eppie M., additional, and Zoghbi, Huda Y., additional

Published
2015
Full Text
View/download PDF

17. Postsymptomatic restoration of SMN rescues the disease phenotype in a mouse model of severe spinal muscular atrophy

Author

Lutz, Cathleen M., Kariya, Shingo, Patruni, Sunita, Osborne, Melissa A., Liu, Don, Henderson, Christopher E., Li, Darrick K., Pellizzoni, Livio, Rojas, Jose, Valenzuela, David M., Murphy, Andrew J., Winberg, Margaret L., and Monani, Umrao R.

Subjects
Gene mutations -- Health aspects -- Research, Motor neurons -- Physiological aspects -- Genetic aspects -- Research, Spinal muscular atrophy -- Genetic aspects -- Risk factors -- Research, Health care industry
Abstract

Spinal muscular atrophy (SMA) is a common neuromuscular disorder in humans. In fact, it is the most frequently inherited cause of infant mortality, being the result of mutations in the survival of motor neuron 1 (SMN1) gene that reduce levels of SMN protein. Restoring levels of SMN protein in individuals with SMA is perceived to be a viable therapeutic option, but the efficacy of such a strategy once symptoms are apparent has not been determined. We have generated mice harboring an inducible Smn rescue allele and used them in a model of SMA to investigate the effects of turning on SMN expression at different time points during the course of the disease. Restoring SMN protein even after disease onset was sufficient to reverse neuromuscular pathology and effect robust rescue of the SMA phenotype. Importantly, our findings also indicated that there was a therapeutic window of opportunity from P4 through P8 defined by the extent of neuromuscular synapse pathology and the ability of motor neurons to respond to SMN induction, following which restoration of the protein to the organism failed to produce therapeutic benefit. Nevertheless, our results suggest that even in severe SMA, timely reinstatement of the SMN protein may halt the progression of the disease and serve as an effective postsymptomatic treatment., Introduction Spinal muscular atrophy (SMA) is a common (~1:6400 newborns), often fatal, pediatric neuromuscular disorder caused by mutations in the survival of the motor neuron 1 (SMN1) gene (1) and, [...]

Published
2011
Full Text
View/download PDF

20. Diminished muscle oxygen uptake and fatigue in spinal muscular atrophy

Author

Montes, Jacqueline, primary, Goodwin, Ashley M., additional, McDermott, Michael P., additional, Uher, David, additional, Hernandez, Feliz Marie, additional, Coutts, Kayla, additional, Cocchi, Julia, additional, Hauschildt, Margarethe, additional, Cornett, Kayla M., additional, Rao, Ashwini K., additional, Monani, Umrao R., additional, Ewing Garber, Carol, additional, and De Vivo, Darryl C., additional

Published
2021
Full Text
View/download PDF

21. An early endothelial cell–specific requirement for Glut1 is revealed in Glut1 deficiency syndrome model mice

Author

Tang, Maoxue, primary, Park, Sarah H., additional, Petri, Sabrina, additional, Yu, Hang, additional, Rueda, Carlos B., additional, Abel, E. Dale, additional, Kim, Carla Y., additional, Hillman, Elizabeth M.C., additional, Li, Fanghua, additional, Lee, Yeojin, additional, Ding, Lei, additional, Jagadish, Smitha, additional, Frankel, Wayne N., additional, De Vivo, Darryl C., additional, and Monani, Umrao R., additional

Published
2021
Full Text
View/download PDF

24. Smn, the spinal muscular atrophy--determining gene product, modulates axon growth and localization of [beta]-actin mRNA in growth cones of motoneurons

Author

Rossoll, Wilfried, Jablonka, Sibylle, Andreassi, Catia, Kroning, Ann-Kathrin, Karle, Kathrin, Monani, Umrao R., and Sendtner, Michael

Subjects
Binding proteins -- Genetic aspects, Binding proteins -- Physiological aspects, Cell research -- Analysis, Gene expression -- Physiological aspects, Messenger RNA -- Genetic aspects, Proteins -- Genetic aspects, Proteins -- Physiological aspects, Regeneration (Biology) -- Genetic aspects, Regeneration (Biology) -- Physiological aspects, Ribonucleotides -- Genetic aspects, Ribonucleotides -- Physiological aspects, Ribosomal proteins -- Genetic aspects, Ribosomal proteins -- Physiological aspects, Spinal muscular atrophy -- Causes of, Biological sciences
Abstract

Spinal muscular atrophy (SMA), a common autosomal recessive form of motoneuron disease in infants and young adults, is caused by mutations in the survival motoneuron 1 (SMN1) gene. The corresponding gene product is part of a multiprotein complex involved in the assembly of spliceosomal small nuclear ribonucleoprotein complexes. It is still not understood why reduced levels of the ubiquitously expressed SMN protein specifically cause motoneuron degeneration. Here, we show that motoneurons isolated from an SMA mouse model exhibit normal survival, but reduced axon growth. Overexpression of Smn or its binding partner, heterogeneous nuclear ribonucleoprotein (hnRNP) R, promotes neurite growth in differentiating PC12 cells. Reduced axon growth in Smn-deficient motoneurons correlates with reduced [beta]-actin protein and mRNA staining in distal axons and growth cones. We also show that hnRNP R associates with the 3' UTR of [beta]-actin mRNA. Together, these data suggest that a complex of Smn with its binding partner hnRNP R interacts with [beta]-actin mRNA and translocates to axons and growth cones of motoneurons.

Published
2003

26. Glut1 Deficiency Syndrome (Glut1DS): State of the art in 2020 and recommendations of the international Glut1DS study group

Author

Klepper, Joerg, primary, Akman, Cigdem, additional, Armeno, Marisa, additional, Auvin, Stéphane, additional, Cervenka, Mackenzie, additional, Cross, Helen J., additional, De Giorgis, Valentina, additional, Della Marina, Adela, additional, Engelstad, Kristin, additional, Heussinger, Nicole, additional, Kossoff, Eric H., additional, Leen, Wilhelmina G., additional, Leiendecker, Baerbel, additional, Monani, Umrao R., additional, Oguni, Hirokazu, additional, Neal, Elizabeth, additional, Pascual, Juan M., additional, Pearson, Toni S., additional, Pons, Roser, additional, Scheffer, Ingrid E., additional, Veggiotti, Pierangelo, additional, Willemsen, Michél, additional, Zuberi, Sameer M., additional, and De Vivo, Darryl C., additional

Published
2020
Full Text
View/download PDF

39. Brain microvasculature defects and Glut1 deficiency syndrome averted by early repletion of the glucose transporter-1 protein

Author

Tang, Maoxue, primary, Gao, Guangping, additional, Rueda, Carlos B., additional, Yu, Hang, additional, Thibodeaux, David N., additional, Awano, Tomoyuki, additional, Engelstad, Kristin M., additional, Sanchez-Quintero, Maria-Jose, additional, Yang, Hong, additional, Li, Fanghua, additional, Li, Huapeng, additional, Su, Qin, additional, Shetler, Kara E., additional, Jones, Lynne, additional, Seo, Ryan, additional, McConathy, Jonathan, additional, Hillman, Elizabeth M., additional, Noebels, Jeffrey L., additional, De Vivo, Darryl C., additional, and Monani, Umrao R., additional

Published
2017
Full Text
View/download PDF

46. Reduced Survival of Motor Neuron (SMN) Protein in Motor Neuronal Progenitors Functions Cell Autonomously to Cause Spinal Muscular Atrophy in Model Mice Expressing the Human Centromeric (SMN2) Gene.

Author

Gyu-Hwan Park, Maeno-Hikichi, Yuka, Awano, Tomoyuki, Landmesser, Lynn T., and Monani, Umrao R.

Subjects
SPINAL muscular atrophy, NEUROMUSCULAR diseases, MOTOR neurons, PROTEINS, LABORATORY mice
Abstract

Spinal muscular atrophy (SMA) is a common (~1:6400) autosomal recessive neuromuscular disorder caused by a paucity of the survival of motor neuron (SMN) protein. Although widely recognized to cause selective spinal motor neuron loss when deficient, the precise cellular site of action of the SMN protein in SMA remains unclear. In this study we sought to determine the consequences of selectively depleting SMN in the motor neurons of model mice. Depleting but not abolishing the protein in motor neuronal progenitors causes an SMA-like phenotype. Neuromuscular weakness in the model mice is accompanied by peripheral as well as central synaptic defects, electrophysiological abnormalities of the neuromuscular junctions, muscle atrophy, and motor neuron degeneration. However, the disease phenotype is more modest than that observed in mice expressing ubiquitously low levels of theSMNprotein, and both symptoms as well as early electrophysiological abnormalities that are readily apparent in neonates were attenuated in an age-dependent manner. We conclude that selective knock-down of SMN in motor neurons is sufficient but may not be necessary to cause a disease phenotype and that targeting these cells will be a requirement of any effective therapeutic strategy. This realization is tempered by the relatively mild SMA phenotype in our model mice, one explanation for which is the presence of normal SMN levels in non-neuronal tissue that serves to modulate disease severity. [ABSTRACT FROM AUTHOR]

Published
2010
Full Text
View/download PDF

48. A single nucleotide difference that alters splicing patterns distinguishes the SMA gene SMN1 from the copy gene SMN2.

Author

Monani, Umrao R., Lorson, Christian L., Parsons, D. William, Prior, Thomas W., Androphy, Elliot J., Burghes, Arthur H. M., and McPherson, John D.

Abstract

Spinal muscular atrophy (SMA) is a recessive disorder characterized by loss of motor neurons in the spinal cord. It is caused by mutations in the telomeric survival motor neuron 1 (SMN1) gene. Alterations within an almost identical copy gene, the centromeric survival motor neuron 2 (SMN2) gene produce no known phenotypic effect. The exons of the two genes differ by just two nucleotides, neither of which alters the encoded amino acids. At the genomic level, only five nucleotides that differentiate the two genes from one another have been reported. The entire genomic sequence of the two genes has not been determined. Thus, differences which might explain why SMN1 is the SMA gene are not readily apparent. In this study, we have completely sequenced and compared genomic clones containing the SMN genes. The two genes show striking similarity, with the homology being unprecedented between two different yet functional genes. The only critical difference in an ~32 kb region between the two SMN genes is the C-->T base change 6 bp inside exon 7. This alteration but not other variations in the SMN genes affects the splicing pattern of the genes. The majority of the transcript from the SMN1 locus is full length, whereas the majority of the transcript produced by the SMN2 locus lacks exon 7. We suggest that the exon 7 nucleotide change affects the activity of an exon splice enhancer. In SMA patients, the loss of SMN1 but the presence of SMN2 results in low levels of full-length SMN transcript and therefore low SMN protein levels which causes SMA. [ABSTRACT FROM AUTHOR]

Published
1999
Full Text
View/download PDF

50. Brain microvasculature defects and Glut1 deficiency syndrome averted by early repletion of the glucose transporter-1 protein

Author

Tang, Maoxue, Gao, Guangping, Rueda, Carlos B., Yu, Hang, Thibodeaux, David Nicholas, Awano, Tomoyuki, Engelstad, Kristin Marie, Sanchez Quintero, Maria Jose, Yang, Hong, Li, Fanghua, Li, Huapeng, Su, Qin, Shetler, Kara E., Jones, Lynne, Seo, Ryan, McConathy, Jonathan, Hillman, Elizabeth M.C., Noebels, Jeffrey L., De Vivo, Darryl C., and Monani, Umrao R.

Subjects
carbohydrates (lipids), endocrine system, Brain--Abnormalities, Glucose, Neurology, Neurobiology, nutritional and metabolic diseases, Microcirculation disorders, hormones, hormone substitutes, and hormone antagonists, 3. Good health
Abstract

Haploinsufficiency of the SLC2A1 gene and paucity of its translated product, the glucose transporter-1 (Glut1) protein, disrupt brain function and cause the neurodevelopmental disorder, Glut1 deficiency syndrome (Glut1 DS). There is little to suggest how reduced Glut1 causes cognitive dysfunction and no optimal treatment for Glut1 DS. We used model mice to demonstrate that low Glut1 protein arrests cerebral angiogenesis, resulting in a profound diminution of the brain microvasculature without compromising the blood–brain barrier. Studies to define the temporal requirements for Glut1 reveal that pre-symptomatic, AAV9-mediated repletion of the protein averts brain microvasculature defects and prevents disease, whereas augmenting the protein late, during adulthood, is devoid of benefit. Still, treatment following symptom onset can be effective; Glut1 repletion in early-symptomatic mutants that have experienced sustained periods of low brain glucose nevertheless restores the cerebral microvasculature and ameliorates disease. Timely Glut1 repletion may thus constitute an effective treatment for Glut1 DS.

Catalog

Books, media, physical & digital resources
See catalog results