Article
Neurosciences
Maria P. P. Miralles, Alba Sansa, Maria Beltran, Rosa M. M. Soler, Ana Garcera
Summary: Spinal Muscular Atrophy (SMA) is a genetic disorder characterized by muscle weakness and degeneration of spinal cord motoneurons. In this study, the NF-kappa B pathway and Gemin3 protein were found to be reduced in SMA mouse and human motoneurons (MNs). Knockdown of Gemin3 resulted in decreased levels of SMN, IKK beta, and RelA proteins, as well as neurite degeneration in MNs.
FRONTIERS IN CELLULAR NEUROSCIENCE
(2022)
Review
Neurosciences
Giulietta M. M. Riboldi, Irene Faravelli, Paola Rinchetti, Francesco Lotti
Summary: Since its identification as the gene responsible for SMA, the functions of the SMN protein have expanded to include roles in RNA processing pathways, mRNA trafficking and translation, axonal transport, endocytosis, and mitochondria metabolism. The SMN complex's activities are regulated by various processes, with post-translational modifications (PTMs) emerging as important regulators. PTMs, such as phosphorylation, methylation, ubiquitination, acetylation, and sumoylation, modulate the pleiotropic functions of the SMN complex. This overview focuses on the PTMs involved in regulating the SMN complex and their implications in SMA pathogenesis.
FRONTIERS IN CELLULAR NEUROSCIENCE
(2023)
Article
Orthopedics
Mengjie Chen, Haibing Chen, Yonggui Gu, Peng Sun, Jianxiong Sun, Haojun Yu, Hongliang Zheng, Donghui Chen
Summary: The study reveals that purinergic receptor P2Y2 plays a crucial role in skeletal muscle atrophy and fibrosis, regulating the activity of muscle cells and fibroblasts after muscle injury to impact the development of the pathology.
BMC MUSCULOSKELETAL DISORDERS
(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)
Review
Biochemistry & Molecular Biology
Raffaella Adami, Daniele Bottai
Summary: Studying neural stem cells (NSCs) from spinal muscular atrophy (SMA) patients is important for identifying new treatment targets and supporting affected patients. However, studying NSCs in living patients is challenging, but can be done using animal models or induced pluripotent stem cells. Therapeutic interventions like NSCs transplantation could improve SMA condition.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(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
Clinical Neurology
Ayse Yesbek Kaymaz, Sevgi Kostel Bal, Gamze Bora, Beril Talim, Alev Ozon, Ayfer Alikasifoglu, Haluk Topaloglu, Hayat Erdem Yurter
Summary: In this study, the components of the IGF-I system in serum and skeletal muscle biopsies of spinal muscular atrophy (SMA) patients were analyzed. The results showed a decrease in IGF-I levels and an increase in IGFBP-5 levels in the serum of SMA patients compared to healthy controls. Increased expression of IGF-I, IGF-I receptor, and IGFBP-5 was detected in skeletal muscle biopsies of SMA patients. These findings suggest alterations in the IGF-I system at both the systemic and tissue-specific levels in SMA patients.
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)
Review
Medicine, General & Internal
Marija Babic, Maria Banovic, Ivana Berecic, Tea Banic, Mirjana Babic Leko, Monika Ulamec, Alisa Junakovic, Janja Kopic, Jadranka Sertic, Nina Barisic, Goran Simic
Summary: Spinal muscular atrophy (SMA) is a rare genetic disorder caused by the deletion or mutation of the SMN1 gene. Nusinersen and risdiplam, the first FDA-approved medications, increase the production of SMN protein from the backup SMN2 gene. The search for prognostic and pharmacodynamic biomarkers in SMA patients' body fluids is ongoing, although more research is needed to identify new biomarkers or combinations of biomarkers.
JOURNAL OF CLINICAL MEDICINE
(2023)
Review
Pharmacology & Pharmacy
Charlotte A. Rene, Robin J. Parks
Summary: Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder caused by mutations in the SMN1 gene, leading to reduced SMN protein levels. SMA patients experience loss of alpha motor neurons in the spinal cord, resulting in skeletal muscle atrophy and other tissue and organ deficits. Onasemnogene abeparvovec, an AAV-based gene therapy, has shown promising results in treating infants and young children with SMA.
Review
Biochemistry & Molecular Biology
Rachel James, Helena Chaytow, Leire M. Ledahawsky, Thomas H. Gillingwater
Summary: SMA is an autosomal recessive motor neuron disease caused by mutations in the SMN1 gene. The development of combinatorial therapies for SMA is necessary, with mitochondria being a relevant target for such therapies. Understanding mitochondrial dysfunction in SMA may lead to the development of targeted mitochondrial therapies with potential benefits for other motor neuron diseases and neurodegenerative disorders.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2021)
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
Alba Sansa, Sandra de la Fuente, Joan X. Comella, Ana Garcera, Rosa M. Soler
Summary: Spinal Muscular Atrophy (SMA) is a severe neuromuscular disorder caused by loss of the Survival Motor Neuron 1 gene (SMN1), leading to degeneration of spinal cord motoneurons and progressive muscular atrophy. The activation of apoptosis in SMA MNs and reduction of Akt phosphorylation may play a crucial role in regulating cell degeneration. Our observations suggest potential mechanisms for controlling cell loss in SMA.
NEUROBIOLOGY OF DISEASE
(2021)
Review
Pediatrics
John W. Day, Kelly Howell, Amy Place, Kimberly Long, Jose Rossello, Nathalie Kertesz, George Nomikos
Summary: Spinal muscular atrophy (SMA) is a genetic neuromuscular condition that affects spinal motor neurons. Current treatments have provided incremental improvements, but there is still a significant disease burden for many patients. The development of a combination therapy targeting myostatin inhibition shows potential for managing SMA.
Review
Cell Biology
Ilaria Signoria, W. Ludo van der Pol, Ewout J. N. Groen
Summary: Spinal muscular atrophy (SMA) is a severe neuromuscular disease with three gene-targeting therapies developed. The existing animal models of SMA, although recapitulate severe types of the disease, still differ from patients in terms of genetics and phenotypes. Therefore, there is a need to generate model systems that better reflect these developments.
DISEASE MODELS & MECHANISMS
(2023)
Article
Biochemistry & Molecular Biology
Felix Leroy, Christopher A. de Solis, Lara M. Boyle, Tobias Bock, Olivia M. Lofaro, Eric W. Buss, Arun Asok, Eric R. Kandel, Steven A. Siegelbaum
Summary: Studies have shown that VIP-expressing interneurons participate in social memory storage by enhancing information transfer and causing long-term depression through release of enkephalin. Additionally, VIP neuron activity in the CA2 region increases selectively during exploration of a novel conspecific.
MOLECULAR PSYCHIATRY
(2022)
Article
Biochemistry & Molecular Biology
Philipp Heher, Massimo Ganassi, Adelheid Weidinger, Elise N. Engquist, Johanna Pruller, Thuy Hang Nguyen, Alexandra Tassin, Anne-Emilie Decleves, Kamel Mamchaoui, Christopher R. S. Banerji, Johannes Grillari, Andrey V. Kozlov, Peter S. Zammit
Summary: FSHD is characterized by oxidative stress induced by DUX4, leading to metabolic dysfunction and impaired mitochondrial function. Increased mitochondrial ROS levels in FSHD muscle cells are associated with elevated steady-state mitochondrial membrane potential. DUX4 triggers mitochondrial membrane polarization, resulting in mitochondrial ROS generation and apoptosis.
Article
Cell Biology
Bruno Della Gaspera, Laure Weill, Christophe Chanoine
Summary: This article summarizes the literature on somite compartmentalization and proposes a model for the evolutionary history of somite compartmentalization. The study suggests that somites in vertebrates have evolved through two major transitions, involving changes in the cell potency of somitic cells and the formation of different vertebrate compartments.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Antoine Besnard, Felix Leroy
Summary: This article discusses how cognition regulates motivated behaviors to fulfill physiological, safety, and social needs, focusing on the role of the lateral septum (LS) in integrating perception, experience, and subcortical modulatory inputs. The authors argue that LS sub-circuits regulate distinct motivated behaviors by integrating neural activity from neocortical, allocortical, and neuromodulatory inputs, and propose that lateral inhibition between LS sub-circuits allows the emergence of functional units that coordinate competing motivated behaviors.
MOLECULAR PSYCHIATRY
(2022)
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)
Article
Biology
Andrea Merseburg, Jacquelin Kasemir, Eric W. Buss, Felix Leroy, Tobias Bock, Alessandro Porro, Anastasia Barnett, Simon E. Troder, Birgit Engeland, Malte Stockebrand, Anna Moroni, Steven A. Siegelbaum, Dirk Isbrandt, Bina Santoro
Summary: De novo mutations in voltage- and ligand-gated channels have been associated with developmental and epileptic encephalopathies resistant to traditional antiseizure medications. Knock-in mouse models replicating these mutations provide valuable insights into disease mechanisms and drug development.
Article
Medicine, Research & Experimental
Swati Dudhal, Lylia Mekzine, Bernard Prudhon, Karishma Soocheta, Bruno Cadot, Kamel Mamchaoui, Delphine Trochet, Marc Bitoun
Summary: Dominant centronuclear myopathy is a rare form of congenital myopathy caused by heterozygous mutations in the DNM2 gene. Specific allele-specific siRNAs have been developed to target the mutated mRNA and show beneficial effects in patient-derived cell lines.
MOLECULAR THERAPY-NUCLEIC ACIDS
(2022)
Article
Chemistry, Multidisciplinary
Muhammad Haseeb Iqbal, Faratiana Jeanne Rosine Revana, Emeline Pradel, Varvara Gribova, Kamel Mamchaoui, Catherine Coirault, Florent Meyer, Fouzia Boulmedais
Summary: The engineering of skeletal muscle tissue is a promising approach for the treatment of muscle injuries and diseases. In this study, a hydrogen-bonded nanofilm was developed using a brushing method to promote muscle tissue development. The nanofilm successfully guided the alignment and differentiation of muscle cells, resulting in the formation of aligned myofibers.
Article
Oncology
Dzhangar Dzhumashev, Andrea Timpanaro, Safa Ali, Andrea J. De Micheli, Kamel Mamchaoui, Ilaria Cascone, Jochen Rossler, Michele Bernasconi
Summary: Rhabdomyosarcoma (RMS) is a common soft tissue sarcoma in childhood and adolescence. This study explored the use of tumor-targeting peptides to selectively deliver drugs to RMS cells. Among the tested peptides, F3 showed strong and specific binding to RMS cells, effective internalization, and delivery of a toxin. The target of F3 peptide, nucleolin, was found to be expressed on the surface of RMS cells. The results suggest that F3 peptide could be a potential therapeutic approach for RMS.
Article
Multidisciplinary Sciences
Wonyul Jang, Dmytro Puchkov, Paula Samso, YongTian Liang, Michal Nadler-Holly, Stephan J. Sigrist, Ulrich Kintscher, Fan Liu, Kamel Mamchaoui, Vincent Mouly, Volker Haucke
Summary: Cells respond to fluctuating nutrient supply by changing organelle dynamics and metabolism. This study reveals that lipid signaling on the endoplasmic reticulum can control mitochondrial morphology and function, enabling cells to adapt to changing nutrient environments.
Article
Medicine, Research & Experimental
Cedric Happi Mbakam, Joel Rousseau, Yaoyao Lu, Anne Bigot, Kamel Mamchaoui, Vincent Mouly, Jacques P. Tremblay
Summary: In this study, researchers used CRISPR-Cas9 prime editing technology to correct a mutation in the DMD gene, resulting in improved editing efficiency and restoration of dystrophin protein expression. Optimization of the reverse transcription template sequence led to a significant increase in the editing percentage of the target nucleotide.
MOLECULAR THERAPY-NUCLEIC ACIDS
(2022)
Article
Medicine, Research & Experimental
Andrea Benzi, Serena Baratto, Cecilia Astigiano, Laura Sturla, Chiara Panicucci, Kamel Mamchaoui, Lizzia Raffaghello, Santina Bruzzone, Elisabetta Gazzerro, Claudio Bruno
Summary: Sarcoglycanopathies are characterized by progressive muscle degeneration. This study reveals the important role of extracellular adenosine triphosphate (eATP) and the purinoceptor P2Y2 in muscle cells from patients with a-/g-sarcoglycanopathy. Understanding the immune-mediated damage associated with these disorders is critical for developing effective gene therapies.
LABORATORY INVESTIGATION
(2023)
Article
Medicine, Research & Experimental
Francesca Tasca, Marcella Brescia, Jin Liu, Josephine M. Janssen, Kamel Mamchaoui, Manuel A. F. V. Goncalves
Summary: Genome editing based on dual CRISPR-Cas9 complexes allows for the removal of specific genomic sequences in living cells, but delivering the required reagents in a synchronous and stoichiometric manner remains challenging. The delivery of forced Cas9 heterodimers or forced CRISPR-Cas9 heterodimers using high-capacity adenovector particles (AdVPs) promotes precise multiplexing genome editing and achieves superior efficiency and accuracy compared to separate delivery of components. The integrated delivery of forced CRISPR-Cas9 heterodimers engages target sequences in a more coordinated fashion, resulting in successful gene editing outcomes.
MOLECULAR THERAPY-NUCLEIC ACIDS
(2023)
Article
Medicine, General & Internal
Cedric Happi Mbakam, Jeanne Roustant, Joel Rousseau, Pouire Yameogo, Yaoyao Lu, Anne Bigot, Kamel Mamchaoui, Vincent Mouly, Gabriel Lamothe, Jacques P. Tremblay
Summary: In this study, the CRISPR-Cas9 Prime editing technology was used to develop strategies to correct frameshift mutations in the DMD gene carrying exon 52 deletion or exons 45 to 52 deletion. Through the use of optimized epegRNAs, specific substitutions, deletions, and insertions were induced in the splice donor sites for exons 51 and 53. These modifications resulted in the skipping of exons 51 and 53 and restored the expression of dystrophin. Overall, Prime editing successfully corrected frameshift mutations in the DMD gene.
FRONTIERS IN MEDICINE
(2023)
Article
Biochemistry & Molecular Biology
Noelia Sofia de Leon Reyes, Paula Sierra Diaz, Ramon Nogueira, Antonia Ruiz-Pino, Yuki Nomura, Christopher A. de Solis, Jay Schulkin, Arun Asok, Felix Leroy
Summary: Adult rodents prefer to interact with novel members of the same species rather than familiar ones. This study identifies neurons in the infra limbic area (ILA) of the mouse prefrontal cortex that express corticotropin-releasing hormone (CRH) and project to the dorsal region of the rostral lateral septum (rLS). The release of CRH during familiar encounters disinhibits rLS neurons, suppressing social interactions with familiar mice and contributing to the preference for social novelty.
