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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
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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

4. 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
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6. 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
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9. 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
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12. 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
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13. 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
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15. 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
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23. 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
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25. Muscle-specific SMN reduction reveals motor neuron-independent disease in spinal muscular atrophy models.

Author

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

Subjects
*SPINAL muscular atrophy, *SPINE diseases, *NERVOUS system, *MOTOR unit, *MYONEURAL junction, *MOTOR neurons, *SKELETAL muscle injuries, *BIOLOGICAL models, *RESEARCH, *SKELETAL muscle, *ANIMAL experimentation, *RESEARCH methodology, *EVALUATION research, *MEDICAL cooperation, *COMPARATIVE studies, *RESEARCH funding, *CARRIER proteins, *MICE
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. [ABSTRACT FROM AUTHOR]

Published
2020
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26. A variant of the Hspa8 synaptic chaperone modifies disease in a SOD1 G86R mouse model of amyotrophic lateral sclerosis.

Author

Takeda T, Her YR, Kim JK, Jha NN, and Monani UR

Abstract

Amyotrophic lateral sclerosis (ALS) is a relatively common and invariably fatal, paralyzing motor neuron disease for which there are few treatment options. ALS is frequently associated with ubiquitin-positive motor neuronal aggregates, a pathology suggestive of perturbed proteostasis. Indeed, cellular chaperones, which are involved in protein trafficking and degradation often underlie familial ALS. Spinal muscular atrophy (SMA) is a second, common paralytic condition resulting from motor neuron loss and muscle atrophy. While SMA is now effectively treated, mechanisms underlying motor neuron degeneration in the disease remain far from clear. To address mechanistic questions about SMA, we recently identified a genetic modifier of the disease. The factor, a G470R variant in the constitutively expressed cellular chaperone, Hspa8, arrested motor neuron loss, prevented the abnormal accumulation of neurofilament aggregates at nerve terminals and suppressed disease. Hspa8 is best known for its role in autophagy. Amongst its many clients is the ALS-associated superoxide dismutase 1 (SOD1) protein. Given its suppression of the SMA phenotype, we tested potential disease-mitigating effects of Hspa8 G470R in a mutant SOD1 mouse model of ALS. Unexpectedly, disease in mutant SOD1 mice expressing the G470R variant was aggravated. Motor performance of the mice deteriorated, muscle atrophy worsened, and lifespan shrunk even further. Paradoxically, SOD1 protein in spinal cord tissue of the mice was dramatically reduced. Our results suggest that Hspa8 modulates the ALS phenotype. However, rather than mitigating disease, the G470R variant exacerbates it., Competing Interests: Declaration of competing interest The authors have declared that there are no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Published
2024
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27. Muscle: an independent contributor to the neuromuscular spinal muscular atrophy disease phenotype.

Author

Jha NN, Kim JK, Her YR, and Monani UR

Subjects
Child, Humans, Muscle, Skeletal, Phenotype, Transcription Factors, Muscular Atrophy, Spinal genetics, Neuromuscular Diseases
Abstract

Spinal muscular atrophy (SMA) is a pediatric-onset neuromuscular disorder caused by insufficient survival motor neuron (SMN) protein. SMN restorative therapies are now approved for the treatment of SMA; however, they are not curative, likely due to a combination of imperfect treatment timing, inadequate SMN augmentation, and failure to optimally target relevant organs. Here, we consider the implications of imperfect treatment administration, focusing specifically on outcomes for skeletal muscle. We examine the evidence that muscle plays a contributing role in driving neuromuscular dysfunction in SMA. Next, we discuss how SMN might regulate the health of myofibers and their progenitors. Finally, we speculate on therapeutic outcomes of failing to raise muscle SMN to healthful levels and present strategies to restore function to this tissue to ensure better treatment results.

Published
2023
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28. Emerging concepts underlying selective neuromuscular dysfunction in infantile-onset spinal muscular atrophy.

Author

Gollapalli K, Kim JK, and Monani UR

Abstract

Infantile-onset spinal muscular atrophy is the quintessential example of a disorder characterized by a predominantly neurodegenerative phenotype that nevertheless stems from perturbations in a housekeeping protein. Resulting from low levels of the Survival of Motor Neuron (SMN) protein, spinal muscular atrophy manifests mainly as a lower motor neuron disease. Why this is so and whether other cell types contribute to the classic spinal muscular atrophy phenotype continue to be the subject of intense investigation and are only now gaining appreciation. Yet, what is emerging is sometimes as puzzling as it is instructive, arguing for a careful re-examination of recent study outcomes, raising questions about established dogma in the field and making the case for a greater focus on milder spinal muscular atrophy models as tools to identify key mechanisms driving selective neuromuscular dysfunction in the disease. This review examines the evidence for novel molecular and cellular mechanisms that have recently been implicated in spinal muscular atrophy, highlights breakthroughs, points out caveats and poses questions that ought to serve as the basis of new investigations to better understand and treat this and other more common neurodegenerative disorders., Competing Interests: None

Published
2021
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