Article
Biochemistry & Molecular Biology
Claudia Malacarne, Mariarita Galbiati, Eleonora Giagnorio, Paola Cavalcante, Franco Salerno, Francesca Andreetta, Cinza Cagnoli, Michela Taiana, Monica Nizzardo, Stefania Corti, Viviana Pensato, Anna Venerando, Cinzia Gellera, Silvia Fenu, Davide Pareyson, Riccardo Masson, Lorenzo Maggi, Eleonora Dalla Bella, Giuseppe Lauria, Renato Mantegazza, Pia Bernasconi, Angelo Poletti, Silvia Bonanno, Stefania Marcuzzo
Summary: Motor neuron diseases (MNDs) are neurodegenerative disorders characterized by upper and/or lower MN loss. Recent research has highlighted the potential role of myomiRs as promising biomarkers in MNDs, with dysregulation of these molecules observed in both mouse models and human patients. Further investigation is needed to explore the therapeutic potential of myomiRs in MND treatment.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Clinical Neurology
Mary Clare McKenna, Philippe Corcia, Philippe Couratier, We Fong Siah, Pierre-Francois Pradat, Peter Bede
Summary: Frontotemporal involvement varies among different motor neuron disease phenotypes, with some cases readily detecting frontotemporal degeneration while others show limited cerebral pathology. Neuroimaging plays an important role in studying extra-motor disease burden, but faces challenges such as sample size limitations and longitudinal study biases.
FRONTIERS IN NEUROLOGY
(2021)
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
Clinical Neurology
Astrid Pechmann, Max Behrens, Katharina Doernbrack, Adrian Tassoni, Sabine Stein, Sibylle Vogt, Daniela Zoeller, Gunther Bernert, Tim Hagenacker, Ulrike Schara-Schmidt, Inge Schwersenz, Maggie C. Walter, Matthias Baumann, Manuela Baumgartner, Marcus Deschauer, Astrid Eisenkoelbl, Marina Flotats-Bastardas, Andreas Hahn, Veronka Horber, Ralf A. Husain, Sabine Illsinger, Jessika Johannsen, Cornelia Koehler, Heike Koelbel, Monika Mueller, Arpad von Moers, Kurt Schlachter, Gudrun Schreiber, Oliver Schwartz, Martin Smitka, Elisabeth Steiner, Eva Stoegmann, Regina Trollmann, Katharina Vill, Claudia Weiss, Gert Wiegand, Andreas Ziegler, Hanns Lochmueller, Janbernd Kirschner
Summary: This study presents real-world evidence on the effects of nusinersen treatment in patients with early-onset spinal muscular atrophy. The findings demonstrate significant improvements in motor function, particularly in children under the age of 2. However, the improvements in bulbar and respiratory function are not equivalent to those in motor function.
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
Neurosciences
Kathrin Kizina, Yakup Akkaya, Daniel Jokisch, Benjamin Stolte, Andreas Totzeck, Juan Munoz-Rosales, Andreas Thimm, Saskia Bolz, Svenja Brakemeier, Refik Pul, Derya Aslan, Jana Hackert, Christoph Kleinschnitz, Tim Hagenacker
Summary: The cognitive performance of adult SMA patients was evaluated using the WAIS-IV test, which showed that most patients had IQ index scores similar to the normal population, but some SMA type-2 patients had lower scores in working memory and perceptual reasoning. This study further demonstrates that SMA is a multi-systemic disease and challenges the hypothesis that SMA patients may improve cognitive skills to compensate for their physical impairment.
Article
Neurosciences
Jannik M. Buettner, Leonie Sowoidnich, Florian Gerstner, Beatriz Blanco-Redondo, Stefan Hallermann, Christian M. Simon
Summary: The activation of the p53 pathway is associated with neuronal degeneration in various neurological disorders, including SMA. Aberrant expression of p53 leads to the selective death of motor neurons in SMA. In this study, the expression of p53 downstream targets c-fos, perp, and fas was investigated in vulnerable motor neurons of SMA mice. Nuclear upregulation of c-Fos protein was observed in degenerating motor neurons in different mouse models of SMA, suggesting that it may serve as a readout for therapeutic approaches targeting neuronal death in SMA and other p53-dependent neurodegenerative diseases.
FRONTIERS IN CELLULAR NEUROSCIENCE
(2022)
Article
Cell Biology
Markus Leo, Linda-Isabell Schmitt, Michael Fleischer, Rebecca Steffen, Cora Osswald, Christoph Kleinschnitz, Tim Hagenacker
Summary: This study investigates the role of spinal astrocytes in the pathogenesis of late-onset SMA forms. Using a mouse model and SMA-like astrocytes, they observed the activation of spinal astrocytes, reduction of certain proteins, and impaired glutamate uptake and potassium uptake. These findings demonstrate the crucial role of spinal astrocytes in the development of late-onset SMA.
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)
Review
Cell Biology
Kishore Gollapalli, Jeong-Ki Kim, Umrao R. Monani
Summary: Infantile-onset spinal muscular atrophy is a neurodegenerative disease caused by a housekeeping protein dysfunction. Research is ongoing to understand why this happens and whether other cell types contribute to the disease. New findings, while sometimes puzzling, advocate for a careful re-examination of study outcomes and emphasize the importance of mild models in identifying key mechanisms driving neuromuscular dysfunction in the disease.
NEURAL REGENERATION RESEARCH
(2021)
Article
Clinical Neurology
P. V. S. Souza, W. B. V. R. Pinto, A. Ricarte, B. M. L. Badia, D. D. Seneor, D. T. Teixeira, L. Caetano, E. A. Goncalves, M. A. T. Chieia, I. B. Farias, E. Bertini, A. S. B. Oliveira
Summary: This study identified a cohort of 20 patients with SMA type 4 in a Brazilian cohort of 227 SMA patients. The most common clinical symptom was limb-girdle muscle weakness, with absent tendon reflexes in 90% of patients and fasciculations in 45% of patients. The majority of patients (80%) had the homozygous deletion of exon 7 in the SMN1 gene, with 60% of them showing four copies of the SMN2 gene.
EUROPEAN JOURNAL OF NEUROLOGY
(2021)
Article
Neurosciences
Elana Molotsky, Yuhong Liu, Andrew P. Lieberman, Diane E. Merry
Summary: This study examines the relationship between neuromuscular junction (NMJ) pathology and vulnerability of fast-twitch motor units in spinal and bulbar muscular atrophy (SBMA) mouse models. The research reveals significantly increased NMJ and myofiber pathology in fast-twitch motor units, along with metabolic dysregulation and myofiber atrophy.
ACTA NEUROPATHOLOGICA COMMUNICATIONS
(2022)
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
Neurosciences
Naemeh Pourshafie, Ester Masati, Amber Lopez, Eric Bunker, Allison Snyder, Nancy A. Edwards, Audrey M. Winkelsas, Kenneth H. Fischbeck, Christopher Grunseich
Summary: This study found that SYNJ2BP is increased in diseased motor neurons and under stress in iPSC-derived motor neurons. Proteomic analysis showed that elevated SYNJ2BP alters the distribution of mitochondria and increases mitochondrial-ER membrane contact sites. Additionally, decreasing SYNJ2BP levels improves mitochondrial oxidative function in diseased motor neurons.
NEUROBIOLOGY OF DISEASE
(2022)
Article
Clinical Neurology
Chaoping Hu, Xihua Li, Yiyun Shi, Xiaomei Zhu, Lei Zhao, Wenhui Li, Shuizhen Zhou, Yi Wang
Summary: This study provides insight into the comprehensive management and profile of different types of SMA patients in China, highlighting the importance of higher SMN2 copies for better survival and ambulation preservation. Patients receiving regular rehabilitation may have better joint function preservation.
FRONTIERS IN NEUROLOGY
(2022)
Article
Multidisciplinary Sciences
Ralda Nehme, Olli Pietilainen, Mykyta Artomov, Matthew Tegtmeyer, Vera Valakh, Leevi Lehtonen, Christina Bell, Tarjinder Singh, Aditi Trehan, John Sherwood, Danielle Manning, Emily Peirent, Rhea Malik, Ellen J. Guss, Derek Hawes, Amanda Beccard, Anne M. Bara, Dane Z. Hazelbaker, Emanuela Zuccaro, Giulio Genovese, Alexander A. Loboda, Anna Neumann, Christina Lilliehook, Outi Kuismin, Eija Hamalainen, Mitja Kurki, Christina M. Hultman, Anna K. Kahler, Joao A. Paulo, Andrea Ganna, Jon Madison, Bruce Cohen, Donna McPhie, Rolf Adolfsson, Roy Perlis, Ricardo Dolmetsch, Samouil Farhi, Steven McCarroll, Steven Hyman, Ben Neale, Lindy E. Barrett, Wade Harper, Aarno Palotie, Mark Daly, Kevin Eggan
Summary: The mechanism by which the 22q11.2 deletion predisposes to psychiatric disease is not well understood. In this study, the authors investigated human neuronal cells and found that the deletion regulates the expression of genes associated with autism, schizophrenia, and synaptic biology. Using induced pluripotent stem cells and CRISPR/Cas9 technology, the researchers found that the deletion alters the abundance of transcripts associated with neurodevelopmental disorders during differentiation into neural progenitor cells. Furthermore, the altered transcripts in excitatory neurons were found to encode presynaptic factors and were associated with genetic risk for schizophrenia.
NATURE COMMUNICATIONS
(2022)
Review
Cell Biology
Caterina Marchioretti, Emanuela Zuccaro, Udai Bhan Pandey, Jessica Rosati, Manuela Basso, Maria Pennuto
Summary: Polyglutamine diseases lead to selective dysfunction and degeneration of specific types of neurons in the central nervous system, and skeletal muscle can also be affected. Skeletal muscle atrophy impacts whole-body metabolism and contributes to the progression of the disease. Animal models of polyglutamine diseases effectively recapitulate skeletal muscle atrophy.
Article
Endocrinology & Metabolism
Maria Santa Rocca, Giovanni Minervini, Cinzia Vinanzi, Alberto Bottacin, Federica Lia, Carlo Foresta, Maria Pennuto, Alberto Ferlin
Summary: This study evaluated the frequency and type of androgen receptor (AR) gene variants in a large cohort of infertile males. The study found that patients with AR gene variants had lower sperm count, higher testosterone concentration, and higher androgen sensitivity index compared to patients without variants. Two novel potentially pathogenic AR variants were identified. Based on these findings, AR sequencing is suggested as a routine genetic test in cases of idiopathic oligozoospermia with high testosterone levels.
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
(2023)
Article
Multidisciplinary Sciences
Caterina Marchioretti, Giulia Zanetti, Marco Pirazzini, Gaia Gherardi, Leonardo Nogara, Roberta Andreotti, Paolo Martini, Lorenzo Marcucci, Marta Canato, Samir R. Nath, Emanuela Zuccaro, Mathilde Chivet, Cristina Mammucari, Marco Pacifici, Anna Raffaello, Rosario Rizzuto, Andrea Mattarei, Maria A. Desbats, Leonardo Salviati, Aram Megighian, Gianni Soraru, Elena Pegoraro, Elisa Belluzzi, Assunta Pozzuoli, Carlo Biz, Pietro Ruggieri, Chiara Romualdi, Andrew P. Lieberman, Gopal J. Babu, Marco Sandri, Bert Blaauw, Manuela Basso, Maria Pennuto
Summary: Marchioretti and colleagues demonstrate that there are reversible alterations in gene expression related to muscle contraction and mitochondrial respiration in the skeletal muscle of SBMA mice and patients. These alterations are accompanied by calcium accumulation inside the mitochondria, motor dysfunction, and late changes in muscle structure. The deregulation of expression of genes involved in excitation-contraction coupling (ECC) occurs with sexual maturity and androgen increase in the serum. Surgical castration and AR silencing alleviate the early and late pathological processes, indicating an androgen-dependent nature of these alterations.
NATURE COMMUNICATIONS
(2023)
Article
Multidisciplinary Sciences
Ramachandran Prakasam, Angela Bonadiman, Roberta Andreotti, Emanuela Zuccaro, Davide Dalfovo, Caterina Marchioretti, Debasmita Tripathy, Gianluca Petris, Eric N. Anderson, Alice Migazzi, Laura Tosatto, Anna Cereseto, Elena Battaglioli, Gianni Soraru, Wooi Fang Lim, Carlo Rinaldi, Fabio Sambataro, Naemeh Pourshafie, Christopher Grunseich, Alessandro Romanel, Udai Bhan Pandey, Andrea Contestabile, Giuseppe Ronzitti, Manuela Basso, Maria Pennuto
Summary: Prakasam and colleagues demonstrate that targeting overexpressed co-activators Lsd1 and Prmt6 with artificial miRNAs can attenuate polyQ-expanded androgen receptor toxicity, ameliorating spinal-bulbar muscular atrophy phenotypes in flies and mice. This study suggests that targeting these co-regulators could be a potential therapeutic strategy for patients with SBMA, as it helps mitigate toxic gain-of-function without exacerbating loss-of-function mechanisms.
NATURE COMMUNICATIONS
(2023)
Article
Multidisciplinary Sciences
Diana Piol, Laura Tosatto, Emanuela Zuccaro, Eric N. Anderson, Antonella Falconieri, Maria J. Polanco, Caterina Marchioretti, Federica Lia, Joseph White, Elisa Bregolin, Giovanni Minervini, Sara Parodi, Xavier Salvatella, Giorgio Arrigoni, Andrea Ballabio, Albert R. La Spada, Silvio C. E. Tosatto, Fabio Sambataro, Diego L. Medina, Udai B. Pandey, Manuela Basso, Maria Plennuto
Summary: Spinal and bulbar muscular atrophy is caused by polyglutamine expansions in androgen receptor, leading to gain-of-function toxicity. This study investigates the phosphorylation of polyglutamine-expanded receptor and its role in neurodegeneration. The researchers find that certain kinases and phosphatases can modify the function and toxicity of the receptor, and targeting these enzymes can potentially be used as a therapeutic approach.
Article
Cell Biology
Emanuela Zuccaro, Caterina Marchioretti, Marco Pirazzini, Maria Pennuto
Summary: Skeletal muscle is the body's most abundant tissue, requiring high levels of energy for proper function. It enables voluntary movement and body posture, which involve different fibers, innervation, energy, and metabolism. This article summarizes the contributions received for the Special Issue on Skeletal Muscle Atrophy: Mechanisms at a Cellular Level, which is divided into three sections: skeletal muscle pathophysiology, disease mechanisms, and therapeutic development.
Article
Cell & Tissue Engineering
Michael F. Wells, James Nemesh, Sulagna Ghosh, Jana M. Mitchell, Max R. Salick, Curtis J. Mello, Daniel Meyer, Olli Pietilainen, Federica Piccioni, Ellen J. Guss, Kavya Raghunathan, Matthew Tegtmeyer, Derek Hawes, Anna Neumann, Kathleen A. Worringer, Daniel Ho, Sravya Kommineni, Karrie Chan, Brant K. Peterson, Joseph J. Raymond, John T. Gold, Marco T. Siekmann, Emanuela Zuccaro, Ralda Nehme, Ajamete Kaykas, Kevin Eggan, Steven A. McCarroll
Summary: Human genome variation plays a role in diversity in neurodevelopmental outcomes and vulnerabilities. In order to understand the underlying molecular and cellular mechanisms, scalable approaches are needed. In this study, a cell villageexperimental platform was used to analyze genetic, molecular, and phenotypic heterogeneity in neural progenitor cells. The results identified a common variant that regulates antiviral IFITM3 expression and explains most inter-individual variation in susceptibility to the Zika virus, as well as potential regulators of progenitor proliferation and differentiation.
