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
Multidisciplinary Sciences
Shengyan Gao, Matthew Esparza, Ishmael Dehghan, Vasilisa Aksenova, Ke Zhang, Kimberly Batten, Max B. Ferretti, Bridget E. Begg, Tolga Cagatay, Jerry W. Shay, Adolfo Garcia-Sastre, Elizabeth J. Goldsmith, Zhijian J. Chen, Mary Dasso, Kristen W. Lynch, Melanie H. Cobb, Beatriz M. A. Fontoura
Summary: This study reveals that the cellular protein kinase TAO2 plays a critical role in the formation and function of nuclear speckles. Depletion or inhibition of TAO2 disrupts nuclear speckle structure and decreases the levels of proteins involved in nuclear speckle assembly and splicing, leading to compromised splicing and nuclear export of influenza virus M mRNA and inhibition of viral replication.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(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)
Review
Neurosciences
Jiaying Qiu, Liucheng Wu, Ruobing Qu, Tao Jiang, Jialin Bai, Lei Sheng, Pengchao Feng, Junjie Sun
Summary: Spinal muscular atrophy (SMA) is a fatal autosomal recessive disorder that previously had no effective treatment. However, with major scientific discoveries and contributions from scientists, the development of the drug nusinersen has brought hope to SMA patients.
FRONTIERS IN CELLULAR NEUROSCIENCE
(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)
Review
Cell Biology
Gabriel P. Faber, Shani Nadav-Eliyahu, Yaron Shav-Tal
Summary: Nuclear speckles are membraneless structures in the cell nucleus that harbor RNAs and proteins, including splicing factors, with complex biophysical properties. Recent genomic analysis combined with microscopy approaches has shed light on their essential functions in gene activity modulation. Nuclear speckles play a role in enhancing gene expression, gene positioning, and RNA processing, and have been implicated in certain diseases, particularly viral infections. They represent an intriguing target for further study and potential therapeutic interventions.
JOURNAL OF CELL SCIENCE
(2022)
Article
Genetics & Heredity
Yogik Onky Silvana Wijaya, Emma Tabe Eko Niba, Hisahide Nishio, Kentaro Okamoto, Hiroyuki Awano, Toshio Saito, Yasuhiro Takeshima, Masakazu Shinohara
Summary: This study examined the effects of high-concentration ASOs and combining two ASOs on splicing efficiency using SMA fibroblasts. The results showed that low or intermediate concentrations of ASOs had better splicing efficiency, while high concentrations of ASOs resulted in the creation of a cryptic exon.
Review
Biochemistry & Molecular Biology
Ibrahim Avsar Ilik, Tugce Aktas
Summary: Complex biochemical reactions in cells are facilitated by compartmentalization within organelles or membrane-less bodies to ensure efficiency and specificity. The nucleus, as one of the earliest discovered organelles, contains various membrane-less bodies. Recent research focuses on the formation of nuclear speckles (NS) and the role of specific proteins such as SON and SRRM2.
Article
Clinical Neurology
Christina Votsi, Pantelitsa Koutsou, Antonis Ververis, Anthi Georghiou, Paschalis Nicolaou, George Tanteles, Kyproula Christodoulou
Summary: This study reports a novel SMN1 splicing variant found in compound heterozygosity with SMN1 exons 7/8 deletion in an infant with severe SMA. The variant was shown to completely lack SMN1 exon 7, validating its disruptive effect on SMN1 splicing. The study also observed the absence of functional SMN1-FL transcript, significant expression of SMN1-d7 transcript, and increased levels of SMN2-FL/SMN2-d7 transcripts.
FRONTIERS IN NEUROLOGY
(2023)
Editorial Material
Neurosciences
Erica L. Gorenberg, James Shorter
Summary: The study identified the RNAs sequestered by tau inclusions and showed related perturbations in nuclear speckles.
Review
Neurosciences
Brunhilde Wirth
Summary: The review highlights the challenging journey from gene discovery to therapy in spinal muscular atrophy (SMA), emphasizing the importance of perseverance in uncovering the biological mechanisms of the disease. Despite the impressive improvements seen with three therapeutic strategies in SMA, there are still many unanswered questions that need to be addressed as discussed in the review.
TRENDS IN NEUROSCIENCES
(2021)
Article
Cell Biology
Sarah E. Hasenson, Ella Alkalay, Mohammad K. Atrash, Alon Boocholez, Julianna Gershbaum, Hodaya Hochberg-Laufer, Yaron Shav-Tal
Summary: Using live-cell imaging, we found that MEG3 lncRNA is a transient resident of nuclear speckles and its association with this nuclear body is modulated by the levels of transcription and splicing activities in the cell.
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
Neurosciences
Chunchu Deng, Sebastian Reinhard, Luisa Hennlein, Janna Eilts, Stefan Sachs, Soeren Doose, Sibylle Jablonka, Markus Sauer, Mehri Moradi, Michael Sendtner
Summary: Using super-resolution microscopy, proximity ligation assay, and live imaging techniques, this study investigated the dynamics of axonal ER and ribosome distribution and activation in a mouse model of SMA. The results showed impaired dynamic remodeling of ER in the axon terminals of Smn-deficient motoneurons, as well as failure of ribosomes to respond to stimulation and associate with axonal ER. These findings suggest that impaired dynamic interplay between ribosomes and ER may contribute to the pathophysiology of SMA and other motoneuron diseases.
TRANSLATIONAL NEURODEGENERATION
(2022)
Article
Medicine, Research & Experimental
Audrey M. Winkelsas, Christopher Grunseich, George G. Harmison, Katarzyna Chwalenia, Carlo Rinaldi, Suzan M. Hammond, Kory Johnson, Melissa Bowerman, Sukrat Arya, Kevin Talbot, Matthew J. Wood, Kenneth H. Fischbeck
Summary: Research shows that ASOs targeting the 50 end of SMN2 can increase SMN mRNA and protein levels by inhibiting SMN2 mRNA decay. Combining 50 UTR ASO with SSO can elevate SMN levels beyond those achieved with SSO alone, offering a new therapeutic target for SMA.
MOLECULAR THERAPY-NUCLEIC ACIDS
(2021)
Review
Biochemistry & Molecular Biology
Laura Trinkle-Mulcahy, Judith E. Sleeman
Article
Cell Biology
Luke W. Thompson, Kim D. Morrison, Sally L. Shirran, Ewout J. N. Groen, Thomas H. Gillingwater, Catherine H. Botting, Judith E. Sleeman
JOURNAL OF CELL SCIENCE
(2018)
Article
Biochemistry & Molecular Biology
Stewart M. Coleman, Alan R. Prescott, Judith E. Sleeman
BIOCHEMICAL JOURNAL
(2014)
Article
Biochemistry & Molecular Biology
Judith Sleeman
BIOCHEMICAL SOCIETY TRANSACTIONS
(2013)
Article
Cell Biology
Judith E. Sleeman, Laura Trinkle-Mulcahy
CURRENT OPINION IN CELL BIOLOGY
(2014)
Article
Developmental Biology
Malcolm E. Fisher, Allyson K. Clelland, Andrew Bain, Richard A. Baldock, Paula Murphy, Helen Downie, Cheryll Tickle, Duncan R. Davidson, Richard A. Buckland
DEVELOPMENTAL BIOLOGY
(2008)
Article
Anatomy & Morphology
Ian C. Dunn, I. Robert Paton, Allyson K. Clelland, Sujith Sebastian, Edward J. Johnson, Lynn McTeir, Dawn Windsor, Adrian Sherman, Helen Sang, Dave W. Burt, Cheryll Tickle, Megan G. Davey
DEVELOPMENTAL DYNAMICS
(2011)
Article
Cell Biology
Alan R. Prescott, Alexandra Bales, John James, Laura Trinkle-Mulcahy, Judith E. Sleeman
JOURNAL OF CELL SCIENCE
(2014)
Article
Cell Biology
Allyson K. Clelland, Nicholas P. Kinnear, Lisa Oram, Julie Burza, Judith E. Sleeman
Article
Cell Biology
Selma Gulyurtlu, Monika S. Magon, Patrick Guest, Panagiotis P. Papavasiliou, Kim D. Morrison, Alan R. Prescott, Judith E. Sleeman
Summary: RNA regulation in mammalian cells requires complex physical compartmentalisation, using structures thought to be formed by liquid-liquid phase separation. Disruption of these structures, such as in the case of myotonic dystrophy type 1 (DM1), can lead to alterations in stress response and biophysical properties of cellular structures, impacting cellular function.
DISEASE MODELS & MECHANISMS
(2022)
Article
Cell Biology
Judith Sleeman
JOURNAL OF CELL SCIENCE
(2007)
Article
Cell Biology
Andrey Sukhodub, Sofija Jovanovic, Qingyou Du, Grant Budas, Allyson K. Clelland, Mei Shen, Kei Sakamoto, Rong Tian, Aleksandar Jovanovic
JOURNAL OF CELLULAR PHYSIOLOGY
(2007)