Article
Biochemistry & Molecular Biology
Anton J. Blatnik, Vicki L. McGovern, Arthur H. M. Burghes
Summary: Proximal spinal muscular atrophy (SMA) is a genetic disorder characterized by motor neuron loss and skeletal muscle atrophy due to deficiency of the essential survival motor neuron (SMN) protein. Therapeutics aimed at increasing SMN protein levels have shown efficacy in treating SMA, but the mechanisms underlying motor neuron loss are still not well understood. Genetics and biochemistry have provided insights into SMA and SMN, from identifying genetic regions to developing potential treatments, but further research is needed to determine critical pathways in SMA.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Cell Biology
Sharon J. Brown, Rachel A. Kline, Silvia A. Synowsky, Sally L. Shirran, Ian Holt, Kelly A. Sillence, Peter Claus, Brunhilde Wirth, Thomas M. Wishart, Heidi R. Fuller
Summary: This study conducted proteomic profiling of skin fibroblasts from different severities of spinal muscular atrophy (SMA) patients. The results showed limited overlap in differentially expressed proteomic profiles among different types of SMA, and the greatest variability was observed within SMA II fibroblasts. Despite limited proteomic overlap, common enriched canonical pathways were identified in two of the three SMA severities. The study also identified protein profiles that may be associated with SMA severity.
Article
Neurosciences
Emily J. Reedich, Martin Kalski, Nicholas Armijo, Gregory A. Cox, Christine J. DiDonato
Summary: Spinal muscular atrophy (SMA) is a neuromuscular disease caused by genetic deficiency of the SMN protein. Studies have shown activation of the p53 and p21 pathways in SMA mice, but they are not primary drivers of motor neuron death in milder SMA mouse models like Smn(2B/-).
EXPERIMENTAL NEUROLOGY
(2021)
Review
Biochemistry & Molecular Biology
Nora Tula Detering, Tobias Schuening, Niko Hensel, Peter Claus
Summary: Spinal muscular atrophy (SMA) is a disease caused by low levels of survival of motoneuron (SMN) protein. Phosphorylation of SMN is considered a key factor affecting SMN function in SMA. Phosphorylation can influence the localization, stability, and functions of SMN, making it a potential important target in SMA treatment strategies.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2022)
Article
Genetics & Heredity
Diou Luo, Natalia Nikolaevna Singh, Ravindra Narayan Singh
Summary: This study investigates the generation mechanism of circRNA in SMN genes. It finds that the presence of introns enhances the rate of circRNA generation and that the exon junction complex plays a role in the generation of circRNAs containing only exons. In addition, SMN circRNAs are preferentially localized in the cytoplasm.
Article
Genetics & Heredity
Marianna Maretina, Anna Egorova, Kristina Lanko, Vladislav Baranov, Anton Kiselev
Summary: This study tested three methods for measuring SMN transcript levels and compared several potential mRNA-based biomarkers in peripheral blood mononuclear cells of SMA patients, SMA carriers, and healthy individuals. The study found that the mean percentage of full-length SMN transcripts determined by semiquantitative and quantitative fluorescence RT-PCR differed significantly between the groups. The relevance of this biomarker was confirmed in a therapeutic experiment targeting the SMN2 gene.
Article
Biochemistry & Molecular Biology
Francesco Errico, Carmen Marino, Manuela Grimaldi, Tommaso Nuzzo, Valentina Bassareo, Valeria Valsecchi, Chiara Panicucci, Elia Di Schiavi, Tommaso Mazza, Claudio Bruno, Adele D'Amico, Manolo Carta, Anna Maria D'Ursi, Enrico Bertini, Livio Pellizzoni, Alessandro Usiello
Summary: In this study, the metabolic effects of Nusinersen in the cerebrospinal fluid (CSF) of spinal muscular atrophy (SMA) patients were characterized using nuclear magnetic resonance (NMR) spectroscopy. The results showed that Nusinersen can modulate amino acid metabolism with distinct downstream metabolic effects according to disease severity. These findings suggest that Nusinersen selectively modulates peripheral organ metabolism in severe SMA patients.
Review
Neurosciences
Jing Li, Xin Li, Liqun Wang, Guode Wu
Summary: This article reports a rare case of a 21-year-old female patient with co-existence of spinal muscular atrophy and moyamoya syndrome. After treatment, the patient's symptoms improved. However, further research is needed to elucidate the relationship between the two diseases.
FRONTIERS IN CELLULAR NEUROSCIENCE
(2022)
Review
Biochemistry & Molecular Biology
Natalia N. Singh, Collin A. O'Leary, Taylor Eich, Walter N. Moss, Ravindra N. Singh
Summary: This article reviews the structural context of exonic and intronic cis-elements that promote or prevent exon 7 recognition in SMN genes. It discusses how structural rearrangements triggered by single nucleotide substitutions can bring drastic changes in SMN2 exon 7 splicing. Potential mechanisms by which inter-intronic structures might impact splicing outcomes are also proposed.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Kwangman Choi, Ansook Yang, Jiyeon Baek, Hyejeong Jeong, Yura Kang, Woosun Baek, Joon-Chul Kim, Mingu Kang, Miri Choi, Youngwook Ham, Min-Jeong Son, Sang-Bae Han, Janghwan Kim, Jae-Hyuk Jang, Jong Seog Ahn, Haihong Shen, Sun-Hee Woo, Jong Heon Kim, Sungchan Cho
Summary: The study identified brefeldin A (BFA) as a strong inducer of SMN protein in SMA fibroblasts, showing a significant role for calcium signaling in the regulation of SMN splicing through modulation of splicing factors. This finding suggests a potential therapeutic strategy for SMA by targeting calcium signaling pathways to upregulate SMN protein expression and rescue splicing defects.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Neurosciences
Marija Farrugia, Neville Vassallo, Ruben J. Cauchi
Summary: Evidence suggests that cell types other than motor neurons, such as glial cells, play a role in both Amyotrophic Lateral Sclerosis (ALS) and Spinal Muscular Atrophy (SMA). This study used a fruit fly model to investigate the specific function of the survival motor neuron (Smn) protein in glial cells. The researchers found that the loss of Smn function in glial cells reduced survival in adult fruit flies but did not affect motor performance or neuromuscular junction morphology. In contrast, the gain of ALS-linked proteins TDP-43, FUS, or C9orf72 in glial cells caused significant defects in motor behavior and reduced survival. These findings highlight the importance of glial cells in SMA disease formation.
Article
Biochemistry & Molecular Biology
Eric William Ottesen, Diou Luo, Natalia Nikolaevna Singh, Ravindra Narayan Singh
Summary: The intronic splicing silencer N1 (ISS-N1) within Survival Motor Neuron 2 (SMN2) intron 7 is a therapeutic target for treating spinal muscular atrophy. Treatment with 100 nM of Anti-N1 resulted in substantial stimulation of SMN2 exon 7 inclusion but also caused significant perturbations in the transcriptome and widespread aberrant splicing. Shorter ISS-N1-targeting ASOs showed a substantial reduction in off-target effects, providing important insights for better ASO design and dosing regimens of ASO-based drugs.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Multidisciplinary Sciences
Lisa Marie Walter, Sebastian Rademacher, Andreas Pich, Peter Claus
Summary: Under stress conditions, nuclear and cytoplasmic actin-cofilin rods are transiently formed to reduce actin filament turnover and ATP hydrolysis. The presence of actin rods in Spinal Muscular Atrophy (SMA) highlights the importance of dysregulated actin dynamics in motoneuron loss. Analysis of the composition of actin rods in a SMA cell culture model revealed binding of proteins involved in ubiquitination, translation, and protein folding, suggesting sequestration of these proteins and impairment of essential cellular functions. Involvement of profilin2 and its upstream effectors RhoA/ROCK in actin rod assembly in SMA indicates detrimental effects on motoneuron homeostasis by affecting actin dynamics and disturbing essential cellular pathways.
SCIENTIFIC REPORTS
(2021)
Article
Clinical Neurology
Tyler R. R. Fortuna, Sukhleen Kour, Anuradha Venkatakrishnan Chimata, Anixa Muinos-Buehl, Eric N. N. Anderson, Charlie H. H. Nelson IV, Caroline Ward, Om Chauhan, Casey O'Brien, Dhivyaa Rajasundaram, Deepa S. S. Rajan, Brunhilde Wirth, Amit Singh, Udai Bhan Pandey
Summary: GEMIN5 is essential for the assembly of snRNPs and its dysfunction is associated with neurodevelopmental disorders. This study reveals that SMN acts as a genetic suppressor of GEMIN5-mediated neurodegeneration by enhancing GEMIN5 expression. The expression patterns of SMN and GEMIN5 are strongly associated in SMA-derived motor neurons with SMN gene mutations.
ACTA NEUROPATHOLOGICA
(2023)
Review
Pediatrics
Zhi-Juan Zhong, Pi-Mei Zheng, Hui-Hong Dou, Ji-Gan Wang
Summary: This study aimed to systematically analyze adverse events (AEs) in the treatment of spinal muscular atrophy (SMA) with Nusinersen in children and adolescents. The study found that Nusinersen-related AEs were rare and it effectively reduced common, serious, and fatal AEs in children and adolescents with SMA.
FRONTIERS IN PEDIATRICS
(2023)
Article
Clinical Neurology
Stanley Iyadurai, W. David Arnold, John T. Kissel, Corey Ruhno, Vicki L. McGovern, Pamela J. Snyder, Thomas W. Prior, Jennifer Roggenbuck, Arthur H. Burghes, Stephen J. Kolb
Meeting Abstract
Clinical Neurology
A. Burghes, V. McGovern, C. Ruhno, T. Prior, P. Snyder, J. Roggenbuck, V. Sansone, J. Kissel
NEUROMUSCULAR DISORDERS
(2017)
Article
Biochemistry & Molecular Biology
Chitra C. Iyer, Kaitlyn M. Corlett, Aurelie Massoni-Laporte, Sandra Duque, Narasimhan Madabusi, Sarah Tisdale, Vicki L. McGovern, Thanh T. Le, Phillip G. Zaworski, W. David Arnold, Livio Pellizzoni, Arthur H. M. Burghes
HUMAN MOLECULAR GENETICS
(2018)
Article
Geriatrics & Gerontology
Kajri A. Sheth, Chitra C. Iyer, Christopher G. Wier, Alexander E. Crum, Anna Bratasz, Stephen J. Kolb, Brian C. Clark, Arthur H. M. Burghes, W. David Arnold
NEUROBIOLOGY OF AGING
(2018)
Retraction
Biochemistry & Molecular Biology
Sarmila Majumder, Saradhadevi Varadharaj, Kalpana Ghoshal, Umrao Monani, Arthur H. M. Burghes, Samson T. Jacob
JOURNAL OF BIOLOGICAL CHEMISTRY
(2018)
Article
Genetics & Heredity
Corey Ruhno, Vicki L. McGovern, Matthew R. Avenarius, Pamela J. Snyder, Thomas W. Prior, Flavia C. Nery, Abdurrahman Muhtaseb, Jennifer S. Roggenbuck, John T. Kissel, Valeria A. Sansone, Jennifer J. Siranosian, Alec J. Johnstone, Pann H. Nwe, Ren Z. Zhang, Kathryn J. Swoboda, Arthur H. M. Burghes
Article
Biochemistry & Molecular Biology
Anton J. Blatnik, Vicki L. McGovern, Thanh T. Le, Chitra C. Iyer, Brian K. Kaspar, Arthur H. M. Burghes
HUMAN MOLECULAR GENETICS
(2020)
Article
Biochemistry & Molecular Biology
Vicki L. McGovern, Kaitlyn M. Kray, W. David Arnold, Sandra Duque, Chitra C. Iyer, Aurelie Massoni-Laporte, Eileen Workman, Aalapi Patel, Daniel J. Battle, Arthur H. M. Burghes
HUMAN MOLECULAR GENETICS
(2020)
Article
Geriatrics & Gerontology
Deepti Chugh, Chitra C. Iyer, Prameela Bobbili, Anton J. Blatnik, Brian K. Kaspar, Kathrin Meyer, Arthur H. M. Burghes, Brian C. Clark, W. David Arnold
Summary: The combination of exercise and FST overexpression has positive effects on neuromuscular junction transmission and muscle mass in aging mice, but does not affect motor unit degeneration.
NEUROBIOLOGY OF AGING
(2021)
Article
Geriatrics & Gerontology
Chitra C. Iyer, Deepti Chugh, Prameela J. Bobbili, Anton J. Blatnik, Alexander E. Crum, Allen F. Yi, Brian K. Kaspar, Kathrin C. Meyer, Arthur H. M. Burghes, W. David Arnold
Summary: Research showed that muscle hypertrophy induced by overexpression of follistatin not only increased muscle weight and torque production, but also counteracted age-related degeneration at the neuromuscular junction in mice.
NEUROBIOLOGY OF AGING
(2021)
Article
Biochemistry & Molecular Biology
Anton J. Blatnik, Vicki L. McGovern, Arthur H. M. Burghes
Summary: Proximal spinal muscular atrophy (SMA) is a genetic disorder characterized by motor neuron loss and skeletal muscle atrophy due to deficiency of the essential survival motor neuron (SMN) protein. Therapeutics aimed at increasing SMN protein levels have shown efficacy in treating SMA, but the mechanisms underlying motor neuron loss are still not well understood. Genetics and biochemistry have provided insights into SMA and SMN, from identifying genetic regions to developing potential treatments, but further research is needed to determine critical pathways in SMA.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Gretchen Thomsen, Arthur H. M. Burghes, Caroline Hsieh, Janet Do, Binh T. T. Chu, Stephanie Perry, Basam Barkho, Petra Kaufmann, Douglas M. Sproule, Douglas E. Feltner, Wendy K. Chung, Vicki L. McGovern, Robert F. Hevner, Miriam Conces, Christopher R. Pierson, Mariacristina Scoto, Francesco Muntoni, Jerry R. Mendell, Kevin D. Foust
Summary: Biodistribution analysis of two patients with spinal muscular atrophy shows widespread onasemnogene abeparvovec DNA, mRNA and SMN protein throughout the central nervous system and peripheral organs following intravenous gene therapy administration. Both patients experienced varying outcomes after receiving the treatment, including improved motor function in one patient and death in the other shortly after administration. The study demonstrates effective distribution, transduction, and expression of onasemnogene abeparvovec throughout the CNS, supporting its potential for restoring SMN expression in individuals with SMA1.
Article
Clinical Neurology
Stephen J. Kolb, Christopher S. Coffey, Jon W. Yankey, Kristin Krosschell, W. David Arnold, Seward B. Rutkove, Kathryn J. Swoboda, Sandra P. Reyna, Ai Sakonju, Basil T. Darras, Richard Shell, Nancy Kuntz, Diana Castro, Julie Parsons, Anne M. Connolly, Claudia A. Chiriboga, Craig McDonald, W. Bryan Burnette, Klaus Werner, Mathula Thangarajh, Perry B. Shieh, Erika Finanger, Merit E. Cudkowicz, Michelle M. McGovern, D. Elizabeth McNeil, Richard Finkel, Susan T. Iannaccone, Edward Kaye, Allison Kingsley, Samantha R. Renusch, Vicki L. McGovern, Xueqian Wang, Phillip G. Zaworski, Thomas W. Prior, Arthur H. M. Burghes, Amy Bartlett, John T. Kissel
ANNALS OF NEUROLOGY
(2017)