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
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
Clinical Neurology
Charlotte Spicer, Ching-Hua Lu, Francesco Catapano, Mariacristina Scoto, Irina Zaharieva, Andrea Malaspina, Jennifer E. Morgan, Linda Greensmith, Francesco Muntoni, Haiyan Zhou
Summary: The study found that the levels of neurofilaments in SMA mice and patients can serve as biomarkers for the disease and indicate response to antisense oligonucleotides treatment. However, lower NfH levels in older SMA patients may limit their application as biomarkers. Further research on additional biomarkers for this group of patients is warranted.
ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY
(2021)
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
Genetics & Heredity
Jan Lejman, Grzegorz Zielinski, Piotr Gawda, Monika Lejman
Summary: Alternative splicing is a crucial mechanism that increases genetic diversity and can be a therapeutic target. Spinal Muscular Atrophy (SMA) is a neurodegenerative disease mainly caused by the homozygous deletion in the SMN1 gene, with 95% of cases attributed to this mutation.
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)
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
Julio Franco-Espin, Alao Gatius, Jose Angel Armengol, Saravanan Arumugam, Mehri Moradi, Michael Sendtner, Jordi Caldero, Lucia Tabares
Summary: SMN protein appears as granules distributed along motor axons at nerve terminals, which co-localize with microtubule-associated protein 1B and neurofilaments. In presynaptic motor terminals, β-actin mRNA, ribosomes, and polysomes, which are key elements of the protein synthesis machinery involved in local translation, are also present. In SMA mice, SMN granules accumulate in areas of neurofilament aggregation, potentially impairing the bi-directional traffic of proteins and organelles between the axon and the presynaptic terminal.
Article
Multidisciplinary Sciences
Jannik M. Buettner, Josiane K. Sime Longang, Florian Gerstner, Katharina S. Apel, Beatriz Blanco-Redondo, Leonie Sowoidnich, Eva Janzen, Tobias Langenhan, Brunhilde Wirth, Christian M. Simon
Summary: Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by reduced survival motor neuron (SMN) protein. By comparing the motor circuit pathology of three SMA mouse models, researchers have identified central excitatory synaptopathy as a key feature of motor circuit pathology in SMA, providing insight for future studies.
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
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
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)
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
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
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
Developmental Biology
Wen Hui Tan, Christoph Winkler
Summary: This study describes a CRISPR/Cas9 homology-directed repair knock-in approach for precise cell lineage tracing via efficient and non-disruptive insertion of Cre drivers controlled by endogenous gene promoters. Using this method, the fate of col10a1 osteoblast progenitors during bone lesion repair in medaka vertebral column was traced, revealing that col10a1 cells at neural arches serve as a mobilizable cellular source for bone repair.
Article
Environmental Sciences
Jiezhang Mo, Miles Teng Wan, Doris Wai-Ting Au, Jingchun Shi, Nathan Tam, Xian Qin, Napo K. M. Cheung, Keng Po Lai, Christoph Winkler, Richard Yuen-Chong Kong, Frauke Seemann
Summary: Benzo[a]pyrene (BaP), a common environmental pollutant, can induce bone toxicity in unexposed offspring. This study found that exposure of medaka to BaP resulted in reduced bone thickness in subsequent generations, and dysregulation of various molecular pathways involved in bone formation and bone resorption. Additionally, epigenetic factors were also implicated in the transgenerational effects of BaP on bone health. These findings highlight the importance of further research on the mechanisms and potential biomarkers of BaP-induced bone disease.
JOURNAL OF ENVIRONMENTAL SCIENCES
(2023)
Article
Cell Biology
Cornelius Schneider, Florian Erhard, Beyenech Binotti, Alexander Buchberger, Jorg Vogel, Utz Fischer
Summary: In starvation conditions, 5'TOP mRNAs undergo low baseline translation with reduced initiation rates instead of being translationally silenced, ensuring a stable 5'TOP mRNA population and allowing fast reversibility of translational repression.
Article
Cell Biology
Luisa Hennlein, Hanaa Ghanawi, Florian Gerstner, Eduardo Palominos Garcia, Ezgi Yildirim, Lena Saal-Bauernschubert, Mehri Moradi, Chunchu Deng, Teresa Klein, Silke Appenzeller, Markus Sauer, Michael Briese, Christian Simon, Michael Sendtner, Sibylle Jablonka
Summary: Hennlein et al. demonstrate a novel role of the actin-bundler PLS3 in mediating correct surface translocation of the neurotrophin receptor TrkB and proper cluster-like formations of voltage-gated Ca2+ channels, which are crucial for development and functional maintenance of motoneurons.
JOURNAL OF CELL BIOLOGY
(2023)
Article
Clinical Neurology
Francesca De Lorenzo, Patrick Luningschror, Jinhan Nam, Liam Beckett, Federica Pilotto, Emilia Galli, Paivi Lindholm, Cora Rudt von Collenberg, Simon Tii Mungwa, Sibylle Jablonka, Julia Kauder, Nadine Thau-Habermann, Susanne Petri, Dan Lindholm, Smita Saxena, Michael Sendtner, Mart Saarma, Merja H. Voutilainen
Summary: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons and has no cure or effective therapy. This study investigates the therapeutic effect of cerebral dopamine neurotrophic factor in rodent models of ALS and shows that it significantly halts disease progression and improves motor behavior. Cerebral dopamine neurotrophic factor rescues motor neurons from endoplasmic reticulum stress-related cell death and enhances motor neuron survival.
Article
Cell Biology
Thomas Andreska, Patrick Luningschror, Daniel Wolf, Rhonda L. McFleder, Maurilyn Ayon-Olivas, Marta Rattka, Christine Drechsler, Veronika Perschin, Robert Blum, Sarah Aufmkolk, Noelia Granado, Rosario Moratalla, Markus Sauer, Camelia Monoranu, Jens Volkmann, Chi Wang Ip, Christian Stigloher, Michael Sendtner
Summary: Parkinson's disease (PD) is characterized by impaired motor control. Cortico-striatal synapses, along with brain-derived neurotrophic factor (BDNF) and TrkB, play crucial roles in motor learning. Dopamine depletion in PD reduces the responsiveness of striatal medium spiny projection neurons (SPNs) to BDNF, leading to impaired TrkB processing and disturbed motor function. Sortilin related VPS10 domain containing receptor 2 (SORCS-2) may protect intracellular TrkB clusters from lysosomal degradation.
Article
Cell Biology
Bita Massih, Alexander Veh, Maren Schenke, Simon Mungwa, Bettina Seeger, Bhuvaneish T. Selvaraj, Siddharthan Chandran, Peter Reinhardt, Jared Sterneckert, Andreas Hermann, Michael Sendtner, Patrick Lueningschroer
Summary: This article introduces a human neuromuscular co-culture system that enables the formation of neuromuscular junctions by differentiating induced pluripotent stem cells into motor neurons and 3D skeletal muscle tissue. The system is suitable for modeling the pathophysiology of motor neuron diseases and has been used to study the synaptic coupling and muscle contraction in Amyotrophic Lateral Sclerosis (ALS). This in vitro model recapitulates aspects of human physiology and is of great importance for studying human motor neurons in health and disease.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2023)
Article
Cell Biology
Patrick Lueningschroer, Thomas Andreska, Alexander Veh, Daniel Wolf, Neha Jadhav Giridhar, Mehri Moradi, Angela Denzel, Michael Sendtner
Summary: The interaction between Calnexin and Fam134b plays a crucial role in targeting TrkB to the cell surface or autophagosomes, regulating the sensitivity of neurons to BDNF.
DEVELOPMENTAL CELL
(2023)
Article
Multidisciplinary Sciences
Josef Panek, Adriana Roithova, Nenad Radivojevic, Michal Sykora, Archana Bairavasundaram Prusty, Nicholas Huston, Han Wan, Anna Marie Pyle, Utz Fischer, David Stanek
Summary: This study reveals that pre-snRNAs have compact structures that prevent binding with Sm proteins during spliceosomal snRNP maturation. Gemin3 and Gemin4 are necessary for rearranging pre-snRNAs to allow interaction with Sm proteins.
NATURE COMMUNICATIONS
(2023)
Article
Multidisciplinary Sciences
Saeede Salehi, Abdolhossein Zare, Gianluca Prezza, Jakob Bader, Cornelius Schneider, Utz Fischer, Felix Meissner, Matthias Mann, Michael Briese, Michael Sendtner
Summary: The neuronal RNA-binding protein Ptbp2 regulates neuronal differentiation by modulating alternative splicing programs in the nucleus. Here, the authors reveal an additional role of cytosolic Ptbp2, which regulates axon growth by fine-tuning the mRNA transport and local synthesis of an RNA-binding protein hnRNP R.
NATURE COMMUNICATIONS
(2023)
Article
Biology
Maria Koerner, Susanne R. Meyer, Gabriella Marincola, Maximilian J. Kern, Clemens Grimm, Christina Schuelein-Voelk, Utz Fischer, Kay Hofmann, Alexander Buchberger
Summary: The ATPase p97, a crucial regulator in various cellular processes, is linked to neuromuscular diseases and cancer. This study identifies the previously unknown FAM104 proteins as a family of p97 interactors. The two human members of the family, VCP nuclear cofactor family member 1 and 2 (VCF1/2), directly bind p97 and associate with p97 complexes in cells. They localize to the nucleus and promote the nuclear import of p97. Loss of VCF1/2 leads to reduced nuclear p97 levels, slow growth, and hypersensitivity to chemical inhibition of p97.
Article
Biology
Maurilyn Ayon-Olivas, Daniel Wolf, Thomas Andreska, Noelia Granado, Patrick Lueningschroer, Chi Wang Ip, Rosario Moratalla, Michael Sendtner
Summary: Motor dysfunction in Parkinson's disease is linked to the depletion of dopamine and altered synaptic plasticity in striatal neurons. Stimulation of dopamine receptor D1 enhances synaptic plasticity in direct pathway spiny projection neurons, while stimulation of dopamine receptor D2 inhibits synaptic plasticity in indirect pathway spiny projection neurons. This study demonstrates the role of tropomyosin receptor kinase B (TrkB) and brain-derived neurotrophic factor (BDNF) in regulating synaptic plasticity at corticostriatal synapses. Dysregulated BDNF/TrkB signaling may contribute to the pathophysiology of both direct and indirect pathway striatal projection neurons in Parkinson's disease.
Article
Cell Biology
Karri Kaivola, Ruth Chia, Jinhui Ding, Memoona Rasheed, Masashi Fujita, Vilas Menon, Ronald L. Walton, Ryan L. Collins, Kimberley Billingsley, Harrison Brand, Michael Talkowski, Xuefang Zhao, Ramita Dewan, Ali Stark, Anindita Ray, Sultana Solaiman, Pilar Alvarez Jerez, Laksh Malik, Ted M. Dawson, Liana S. Rosenthal, Marilyn S. Albert, Olga Pletnikova, Juan C. Troncoso, Mario Maselis, Julia Keith, Eric Int LBD Genomics Consortium, Ali Int ALS FTD Consortium, Pentti PROSPECT Consortium, Toshiko Tanaka, Eric Topol, Ali Torkamani, Pentti Tienari, Tatiana M. Foroud, Bernardino Ghetti, John E. Landers, Mina Rtyen, Huw R. Morris, John A. Hardy, Letizia Mazzini, Sandra D'Alfonso, Cristina Moglia, Andrea Calvo, Geidy E. Serrano, Thomas G. Beach, Tanis Ferman, Neill R. Graff-Radford, Bradley F. Boeve, Zbigniew K. Wszolek, Dennis W. Dickson, Adriano Chio, David A. Bennett, Philip L. De Jager, Owen A. Ross, Clifton L. Dalgard, J. Raphael Gibbs, Bryan J. Traynor, Sonja W. Scholz
Summary: This study characterized the role of structural variants in Lewy body dementia (LBD) and frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS). The researchers discovered a novel risk locus for LBD and found associations between known structural variants and FTD/ALS. Rare pathogenic structural variants were also identified in both LBD and FTD/ALS. The study provides a catalog of structural variants for further understanding of the pathogenesis of these forms of dementia.
Article
Multidisciplinary Sciences
Michael Trumpp, Wen Hui Tan, Wiktor Burdzinski, Yara Basler, Jerome Jatzlau, Petra Knaus, Christoph Winkler
Summary: Activin and BMP signaling are important in vertebrate organ formation and tissue homeostasis. A mutation in BMP type I receptor leads to abnormal inflammation and ossification in FOP patients. The Japanese medaka fish can serve as a FOP animal model to investigate the mechanisms underlying the disease.