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.
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)
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)
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.
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
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
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
M. A. Maretina, K. R. Valetdinova, N. A. Tsyganova, A. A. Egorova, V. S. Ovechkina, H. B. Schioth, S. M. Zakian, V. S. Baranov, A. Kiselev
Summary: The study found that certain genes in cells from spinal muscular atrophy patients have different methylation patterns compared to cells from healthy individuals, which helps deepen the understanding of the disease pathogenesis.
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.
Article
Genetics & Heredity
Junjie Sun, Jiaying Qiu, Qiongxia Yang, Qianqian Ju, Ruobing Qu, Xu Wang, Liucheng Wu, Lingyan Xing
Summary: This study provides a single-cell atlas of the spinal cord in severe SMA mice, revealing different cell types and their differentially expressed genes. The communication between different cell types in the SMA spinal cord was significantly reduced. A subpopulation of vascular fibroblasts showed the most significant change, possibly leading to vascular defects and widespread protein synthesis and energy metabolism reductions in SMA mice.
Article
Clinical Neurology
Domenico D'Amico, Olivier Biondi, Camille Januel, Cynthia Bezier, Delphine Sapaly, Zoe Clerc, Mirella El Khoury, Venkat Krishnan Sundaram, Leo Houdebine, Thibaut Josse, Bruno Della Gaspera, Cecile Martinat, Charbel Massaad, Laure Weill, Frederic Charbonnier
Summary: This study reveals that the IRE1 alpha/XBP1 branch of the unfolded protein response is disrupted in spinal muscular atrophy (SMA), with a depletion of XBP1s contributing to SMA pathogenesis. Rebalancing XBP1s expression can induce SMN expression and protect spinal motor neurons in severe SMA-like mice.
NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY
(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
Clinical Neurology
Ying Hu, Ling Wei, Aonan Li, Tingting Liu, Yubao Jiang, Chengjuan Xie, Kai Wang
Summary: This study aimed to assess the cognitive profile of adult Chinese patients with SMA and explore the association between clinical features and cognitive ability, particularly executive function. The results showed that SMA patients had impaired executive function, which was correlated with a younger age at onset, poorer motor function, and higher levels of anxiety and depression.
FRONTIERS IN NEUROLOGY
(2023)
Article
Biochemistry & Molecular Biology
Laura Bianchi, Maria Sframeli, Lorenza Vantaggiato, Gian Luca Vita, Annamaria Ciranni, Francesca Polito, Rosaria Oteri, Eloisa Gitto, Fabrizio Di Giuseppe, Stefania Angelucci, Antonio Versaci, Sonia Messina, Giuseppe Vita, Luca Bini, M'hammed Aguennouz
Summary: Treatment with nusinersen in SMA type 1 patients led to a reversal trend of CSF protein profiles towards those of control donors, with significant up-regulation of apolipoprotein A1 and apolipoprotein E, as well as consistent changes in transthyretin proteoforms. These proteins play crucial roles in molecular processes aberrant in SMA, suggesting that they could serve as valuable biomarkers for assessing patient responsiveness and disease progression.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Cell Biology
Angela Koh, Menachem Viktor Sarusie, Jurgen Ohmer, Utz Fischer, Christoph Winkler, Thorsten Wohland
Summary: The research found that a decrease in SMN protein levels in patients with Spinal Muscular Atrophy may lead to transcript splicing defects, rather than active transport in axons; SMN acts as a chaperone for the assembly of snRNP and mRNP complexes in motor neurons, playing an important role.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Review
Biochemistry & Molecular Biology
N. N. Singh, M. D. Howell, E. J. Androphy, R. N. Singh
Article
Biochemistry & Molecular Biology
Eric W. Ottesen, Natalia N. Singh, Diou Luo, Ravindra N. Singh
NUCLEIC ACIDS RESEARCH
(2018)
Article
Biochemistry & Molecular Biology
Eric W. Ottesen, Diou Luo, Joonbae Seo, Natalia N. Singh, Ravindra N. Singh
NUCLEIC ACIDS RESEARCH
(2019)
Review
Biochemistry & Molecular Biology
Ravindra N. Singh, Natalia N. Singh
BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS
(2019)
Article
Biochemistry & Molecular Biology
Natalia N. Singh, Ravindra N. Singh
BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS
(2019)
Editorial Material
Biochemistry & Molecular Biology
Francisco E. Baralle, Ravindra N. Singh, Stefan Stamm
BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS
(2019)
Editorial Material
Chemistry, Medicinal
Ravindra N. Singh
FUTURE MEDICINAL CHEMISTRY
(2019)
Review
Biochemistry & Molecular Biology
Natalia N. Singh, Eric W. Ottesen, Ravindra N. Singh
BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS
(2020)
Review
Pharmacology & Pharmacy
Ravindra N. Singh, Joonbae Seo, Natalia N. Singh
EXPERT OPINION ON THERAPEUTIC TARGETS
(2020)
Review
Cell Biology
Eric W. Ottesen, Ravindra N. Singh
CELLULAR SIGNALLING
(2020)
Article
Biochemistry & Molecular Biology
Natalia N. Singh, Shaine Hoffman, Prabhakara P. Reddi, Ravindra N. Singh
Summary: Spinal muscular atrophy (SMA) is a major genetic disorder associated with infant mortality, primarily caused by deletions or mutations in the Survival Motor Neuron 1 (SMN1) gene. The spectrum of SMA ranges from prenatal death to survival into adulthood, with all tissues potentially affected.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
(2021)
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
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
Biochemistry & Molecular Biology
Eric W. Ottesen, Natalia N. Singh, Diou Luo, Bailey Kaas, Benjamin J. Gillette, Joonbae Seo, Hannah J. Jorgensen, Ravindra N. Singh
Summary: Designing an RNA-interacting molecule that exhibits both high therapeutic efficacy and concentration-specific specificity remains challenging. Risdiplam and branaplam, two small molecules approved for the treatment of spinal muscular atrophy (SMA) and undergoing clinical trials, respectively, are able to restore the inclusion of Survival Motor Neuron 2 (SMN2) exon 7. However, the transcriptome-wide off-target effects of these compounds in SMA patient cells reveal concentration-dependent changes and perturbations in gene expression, splicing events, and cellular pathways. Understanding these off-target effects and their mechanisms can guide the development of improved dosing regimens and future small molecule therapeutics for splicing modulation.
NUCLEIC ACIDS RESEARCH
(2023)
Review
Neurosciences
Ravindra N. Singh, Eric W. Ottesen, Natalia N. Singh
NEUROSCIENCE INSIGHTS
(2020)