Article
Clinical Neurology
Marzieh Khani, Shahriar Nafissi, Hosein Shamshiri, Hamidreza Moazzeni, Hanieh Taheri, Mehdi Sadeghi, Najmeh Salehi, Fereshteh Chitsazian, Elahe Elahi
Summary: This study reports the identification of UBA1 as a novel causative gene for SBMA. A missense mutation in UBA1 was found to be the possible cause of non-Kennedy SBMA in a pedigree. The study also discusses the contribution of UBA1 to the etiology of XL-SMA.
EUROPEAN JOURNAL OF NEUROLOGY
(2022)
Article
Cell Biology
Peipei Ding, Yanqing Xu, Luying Li, Xinyue Lv, Ling Li, Jianfeng Chen, Danlei Zhou, Xiaochao Wang, Qi Wang, Wei Zhang, Tian Liao, Qing-Hai Ji, Qun-Ying Lei, Weiguo Hu
Summary: This study uncovers the activation of C5 complement within tumor cells, which affects colorectal tumorigenesis by regulating the stability of beta-catenin. The findings provide a potential target for tumor prevention and treatment.
Article
Multidisciplinary Sciences
Niko Hensel, Federica Cieri, Pamela Santonicola, Ines Tapken, Tobias Schuening, Michela Taiana, Elisa Pagliari, Antonia Joseph, Silke Fischer, Natascha Heidrich, Hella Brinkmann, Sabrina Kubinski, Anke K. Bergmann, Manuela F. Richter, Klaus Jung, Stefania Corti, Elia Di Schiavi, Peter Claus
Summary: Spinal muscular atrophy (SMA) is a motor neuron disease caused by deletions of the SMN1 gene and low SMN protein levels. Recent studies have identified altered signaling networks in SMA, with two clusters structured around AKT, 14-3-3 zeta/delta, and a major hub connecting both clusters, B-Raf. Down-regulation of B-Raf and 14-3-3 zeta/delta in SMA mice and patients suggests a conserved mechanism across species, with potential therapeutic implications for motoneuron survival.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Genetics & Heredity
G. Perez-Siles, M. Ellis, A. Ashe, B. Grosz, S. Vucic, M. C. Kiernan, K. A. Morris, S. W. Reddel, M. L. Kennerson
Summary: Spinal Muscular Atrophy (SMA) is characterized by muscular atrophy and weakness due to genetic mutations. This study identified CAPN1 as a novel gene associated with SMA4 phenotype and found that CAPN1 dysfunction may play a role in SMA4 pathophysiology. The findings expand our understanding of CAPN1 mutation disorders and their phenotypes.
FRONTIERS IN GENETICS
(2022)
Article
Biochemistry & Molecular Biology
Kishore K. Joshi, Tarmie L. Matlack, Stephanie Pyonteck, Mehul Vora, Ralph Menzel, Christopher Rongo
Summary: Metazoans utilize protein homeostasis pathways to respond to adverse conditions, with the nervous system playing a role in regulating proteostasis in different tissues. This study reveals that Caenorhabditis elegans uses biogenic amine neurotransmitters to modulate UPS proteostasis in epithelia by promoting eicosanoid production through P450 monooxygenases, ultimately maintaining protein turnover.
Article
Neurosciences
Mayumi Kataoka, Kentaro Sahashi, Koyo Tsujikawa, Jun-ichi Takeda, Tomoki Hirunagi, Madoka Iida, Masahisa Katsuno
Summary: Lower motor neuron degeneration is a pathological feature of spinal muscular atrophy (SMA), a hereditary motor neuron disease caused by loss of the SMN1 gene and resulting deficiency of SMN protein. The molecular mechanisms underlying motor neuron degeneration are still unknown. In this study, transcriptome analysis of isolated embryonic motor neurons from SMA model mice revealed dysregulation of cell-type specific gene expression, with Aldh1a2 identified as a key gene for lower motor neuron development. Knockdown of Aldh1a2 in primary spinal motor neuron cultures led to axonal spheroid formation and neurodegeneration, similar to histopathological changes observed in human and animal models. Conversely, Aldh1a2 rescued these pathological features in SMA mouse embryos. These findings suggest that dysregulation of Aldh1a2 during development enhances lower motor neuron vulnerability in SMA.
NEUROSCIENCE RESEARCH
(2023)
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
Xingxing Xu, Jiaojiao Wang, Siyu Du, Xiya Shen, Jiashu Lian, Jian Zhou, Mianxian Wang, Wenjin Feng, Zhaoting Lv, Junzhe Zhu, Lingting Jin, Huankun Sun, Lihao Wu, Xiaoning Wang, Haoyu Qiu, Wei Wang, Honglin Teng, Ying Wang, Zhihui Huang
Summary: Our study reveals that YAP signaling plays an important role in the regulation of glutamate homeostasis through the beta-catenin/EAAT2 pathway in astrocytes. This finding provides new insights into the pathogenesis of brain diseases related to EAAT2 dysfunction or dysregulation and may contribute to the development of clinical strategies.
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
Biology
Zhi Liu, Tian Chen, Sicheng Zhang, Tianfang Yang, Yun Gong, Hong-Wen Deng, Ding Bai, Weidong Tian, YiPing Chen
Summary: This study identified a population of adipocytes, named Wnt(+) adipocytes, that exhibit persistent activity of the Wnt/β-catenin signaling pathway. The activation of this pathway is independent of Wnt ligands and receptors but relies on the AKT/mTOR pathway and is crucial for cell survival. These adipocytes have distinct transcriptomic and genomic signatures from classical adipocytes and can be induced from various sources of mesenchymal stromal cells. Furthermore, they convert into beige adipocytes directly and are required for beige fat recruitment under thermal challenge.
Review
Neurosciences
Medha Sengupta, Anna Pluciennik, Diane E. Merry
Summary: Spinal and bulbar muscular atrophy (SBMA) is a neurodegenerative disease caused by the expansion of a polyglutamine-encoding CAG tract in the androgen receptor gene. The ubiquitin-proteasome system (UPS) plays a crucial role in SBMA and may be a potential therapeutic target.
FRONTIERS IN MOLECULAR NEUROSCIENCE
(2022)
Article
Cell Biology
Zimin Xiang, Shuai Zhang, Xiaodong Yao, Libin Xu, Jianwei Hu, Chenghui Yin, Jianmei Chen, Hao Xu
Summary: Resveratrol can promote function recovery and axonal regeneration, improve histological damage, and inhibit apoptosis level after SCI by regulating the Wnt/beta-catenin signaling pathway. This study expanded the regulatory mechanism of resveratrol in SCI injury.
Article
Cell Biology
Yong Ji, Yiqian Liu, Changchun Sun, Lijiang Yu, Zhao Wang, Xu Du, Wu Yang, Chenggong Zhang, Chunmu Tao, Jianjiang Wang, Xi Yang, Sun Di, Yufeng Huang
Summary: Mutations in the Wnt/beta-catenin signaling pathway upstream lead to abnormal activation in colon cancer, and ADCK1 plays a crucial role in promoting cancer progression by interacting with TCF4 to activate the beta-catenin/TCF pathway. This research identifies potential therapeutic targets for colon cancer treatment.
CELL DEATH & DISEASE
(2021)
Article
Biochemistry & Molecular Biology
Kai Li, Yi Niu, Yichuan Yuan, Jiliang Qiu, Yunxing Shi, Chengrui Zhong, Zhiyu Qiu, Keren Li, Zhu Lin, Zhenkun Huang, Chao Zhang, Dinglan Zuo, Wei He, Yunfei Yuan, Binkui Li
Summary: Insufficient thermal ablation can promote the progression of hepatocellular carcinoma (HCC) and upregulate the E3 ligase Nedd4. Nedd4 enhances the TGF-beta signal transduction, promoting tumor growth and metastasis. High Nedd4 expression correlates with aggressive tumor phenotypes and poor prognosis in HCC patients.
Article
Biochemistry & Molecular Biology
Byeong-Yun Ahn, Myong-Ho Jeong, Jung-Hoon Pyun, Hyeon-Ju Jeong, Tuan Anh Vuong, Ju-Hyeon Bae, Subin An, Su Woo Kim, Yong Kee Kim, Dongryeol Ryu, Hyun-Ji Kim, Hana Cho, Gyu-Un Bae, Jong-Sun Kang
Summary: PRMT7 plays an important role in cardiac hypertrophy and fibrosis. Overexpression of PRMT7 can alleviate cellular hypertrophic response, while depletion of PRMT7 exacerbates hypertrophic response. Transcriptome analysis reveals altered gene expression profile related to Wnt signaling pathway in PRMT7-deficient hearts.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2022)
Letter
Medicine, General & Internal
Thomas H. Gillingwater, Catherine McWilliam, Iain Horrocks, Kenneth McWilliam, Mark Hamilton, Elaine Fletcher, Nicola Williams, Sarah Smith, Simon H. Parson
SCOTTISH MEDICAL JOURNAL
(2022)
Article
Clinical Neurology
Charlotte H. Hulme, Heidi R. Fuller, John Riddell, Sally L. Shirran, Catherine H. Botting, Aheed Osman, Karina T. Wright
Summary: The study aimed to characterize the blood proteome following spinal cord injury using rat models and identified differentially regulated pathways in response to SCI, providing insights for future research in developing therapeutic interventions and prognostic indicators.
Article
Medieval & Renaissance Studies
Luke John Murphy, Heidi R. Fuller, Peter L. T. Willan, Monte A. Gates
Summary: This article analyzes medieval descriptions of the blood eagle ritual using modern anatomical knowledge and the latest archaeological and historical research. The authors argue that the fullest form of the blood eagle would have been possible but would have resulted in the victim's death early on. They also suggest that the ritual would have been part of a wider cultural practice aimed at maintaining the social status of the ritual's commissioner after the death of a male relative.
SPECULUM-A JOURNAL OF MEDIEVAL STUDIES
(2022)
Article
Clinical Neurology
Claudia S. Bauer, Rebecca N. Cohen, Francesca Sironi, Matthew R. Livesey, Thomas H. Gillingwater, J. Robin Highley, Daniel J. Fillingham, Ian Coldicott, Emma F. Smith, Yolanda B. Gibson, Christopher P. Webster, Andrew J. Grierson, Caterina Bendotti, Kurt J. De Vos
Summary: A GGGGCC hexanucleotide repeat expansion in the C9ORF72 gene is the main genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. This study shows that C9orf72 protein interacts with the synapsin family of synaptic vesicle proteins, and C9orf72 deficiency reduces the number of excitatory synapses and synapsin levels, leading to synaptic dysfunction.
ACTA NEUROPATHOLOGICA
(2022)
Article
Biochemistry & Molecular Biology
Mohannad Ghanem, Sharon J. Brown, Aysha E. A. T. Mohamed, Heidi R. Fuller
Summary: In this study, a meta-summary approach was used to analyze COVID-19 biomarker datasets, identifying a panel of 17 proteins showing consistent changes. Bioinformatics analysis revealed their involvement in inflammatory responses and compromised integrity of physiological systems. Additionally, upstream regulators of COVID-19 severity biomarkers, including compounds under investigation for COVID-19 treatment, were identified.
Article
Anatomy & Morphology
Stephen D. Cahalan, Justin D. Perkins, Ines Boehm, Ross A. Jones, Thomas H. Gillingwater, Richard J. Piercy
Summary: Morphological study of the neuromuscular junction is crucial for understanding synaptic biology and neuromuscular disease pathogenesis. While previous studies have focused on small mammals, this research successfully developed a technique for dissecting and analyzing NMJs in large mammalian distal limb muscles, specifically in horses. The study demonstrates the distinctive morphology of NMJs in the equine soleus muscle compared to other muscles.
JOURNAL OF ANATOMY
(2022)
Review
Cell Biology
Rachel A. Kline, Lena Loesslein, Dominic Kurian, Judit Aguilar Marti, Samantha L. Eaton, Felipe A. Court, Thomas H. Gillingwater, Thomas M. Wishart
Summary: Recent advances in proteomic technologies have enabled unprecedented assessment of molecular composition in various sample types. However, careful consideration is required when applying these technologies, including methodological selection and analysis workflow. The effectiveness of most proteomics screens is hindered by inadequate analyses, rather than technical limitations. Furthermore, studying progressive neurodegenerative conditions presents inherent difficulties that should be addressed.
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
Cell Biology
Emily C. Storey, Heidi R. Fuller
Summary: Mutations in genes encoding proteins associated with the LINC complex can cause different diseases, but the relationship between genetic mutations and clinical phenotypes is still unclear. LMNA is the only gene where mutations commonly cause distinct conditions and there is no clear genotype-phenotype correlation. These findings provide insights into the role of LINC-complex proteins in human disease and guide future gene-targeted therapies.
Article
Clinical Neurology
Wolfgang Muller-Felber, Astrid Blaschek, Oliver Schwartz, Dieter Glaser, Uta Nennstiel, Inken Brockow, Brunhilde Wirth, Siegfried Burggraf, Wulf Roschinger, Marc Becker, Jurgen Durner, Katja Eggermann, Heike Kolbel, Christine Muller, Iris Hannibal, Bernd Olgemoller, Ulrike Schara, Arpad von Moers, Regina Trollmann, Jessika Johannssen, Andreas Ziegler, Sebahattin Cirak, Andreas Hahn, Maja von Der Hagen, Claudia Weiss, Gudrun Schreiber, Marina Flotats-Bastardas, Hans Hartmann, Sabine Illsinger, Astrid Pechmann, Veronka Horber, Jan Kirschner, Cornelia Kohler, Benedikt Winter, Johannes Friese, Katharina Vill
Summary: With the availability of targeted therapies for spinal muscular atrophy, efforts are being made worldwide to incorporate screening for this condition in general newborn screening. In Germany, after pilot projects from 2018-2021, spinal muscular atrophy screening was included in the general newborn screening from October 2021. Criteria for follow-up were developed in collaboration with key stakeholders to ensure a smooth transition. Although there were initial false positive findings during the transition, they were subsequently resolved through optimization of the screening method in the laboratories involved. The timing of diagnosis and therapy initiation did not significantly differ from the pilot project.
JOURNAL OF NEUROMUSCULAR DISEASES
(2023)
Article
Biochemistry & Molecular Biology
Sharon J. Brown, Darija Soltic, Silvia A. Synowsky, Sally L. Shirran, Ellie Chilcott, Hannah K. Shorrock, Thomas H. Gillingwater, Rafael J. Yanez-Munoz, Bernard Schneider, Melissa Bowerman, Heidi R. Fuller
Summary: Structural, functional and molecular cardiac defects have been found in SMA patients and mouse models. Proteomics analysis showed widespread molecular defects in severe SMA mice. This study investigated if similar changes can be found in less severe SMA mouse models, and found that many proteins related to cardiovascular development and function were dysregulated.
HUMAN MOLECULAR GENETICS
(2023)
Article
Medicine, Research & Experimental
Yu-Ting Huang, Hannah R. Crick, Helena Chaytow, Dinja van der Hoorn, Abrar Alhindi, Ross A. Jones, Ralph D. Hector, Stuart R. Cobb, Thomas H. Gillingwater
Summary: Neuromuscular junction stability is crucial for the treatment of various diseases, and this study developed a novel gene delivery vector to achieve targeted overexpression of DOK7 in skeletal muscle. The results showed that this method can safely achieve DOK7 overexpression and enlarge both the pre- and post-synaptic components of the neuromuscular junction without causing denervation.
MOLECULAR THERAPY-NUCLEIC ACIDS
(2023)
Article
Biochemistry & Molecular Biology
Yaron Trink, Achia Urbach, Benjamin Dekel, Peter Hohenstein, Jacob Goldberger, Tomer Kalisky
Summary: Wilms' tumors are pediatric malignancies that arise from faulty kidney development. Computational approaches were used to characterize the continuous heterogeneity in high-risk blastemal-type Wilms' tumors, revealing a triangle-shaped continuum in latent space bounded by three tumor archetypes with different characteristics resembling developmental stages of the fetal kidney. These findings provide insights into the relationship between Wilms' tumors and kidney development, and have the potential to improve tumor stratification and classification strategies.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Medicine, Research & Experimental
Hemanth R. Nelvagal, Samantha L. Eaton, Sophie H. Wang, Elizabeth M. Eultgen, Keigo Takahashi, Steven Q. Le, Rachel Nesbitt, Joshua T. Dearborn, Nicholas Siano, Ana C. Puhl, Patricia Dickson, Gerard Thompson, Fraser Murdoch, Paul M. Brennan, Mark Gray, Stephen N. Greenhalgh, Peter Tennant, Rachael Gregson, Eddie Clutton, James Nixon, Chris Proudfoot, Stefano Guido, Simon G. Lillico, C. Bruce A. Whitelaw, Jui-Yun Lu, Sandra L. Hofmann, Sean Ekins, Mark S. Sands, Thomas M. Wishart, Jonathan D. Cooper
Summary: CLN1 disease, a fatal neurodegenerative lysosomal storage disorder, has proven challenging to treat. This study tested the efficacy of enzyme replacement therapy (ERT) and found that intracerebrovascular administration of recombinant PPT1 showed therapeutic benefits in mouse and sheep models. The findings highlight the feasibility and therapeutic efficacy of ERT and emphasize the importance of cross-species research in developing successful treatment strategies.
JOURNAL OF CLINICAL INVESTIGATION
(2022)