Review
Biochemistry & Molecular Biology
Pavlina Hemerkova, Martin Valis
Summary: ALS is a neurodegenerative disease that affects motor neurons and currently has no cure. Free oxygen radicals are known to play a role in the pathogenesis of ALS, while antioxidant enzymes like SOD1 are crucial for antioxidant protection.
Article
Biochemistry & Molecular Biology
Venkatesan Santhanam, Priya Modi, Umesh K. Mishra, Ishrat Jahan, Namakkal G. Ramesh, Shashank Deep
Summary: In this study, the first iminosugar that inhibits superoxide dismutase fibrillation associated with ALS is reported. Novel triazole and tetrazole embedded iminosugars were successfully synthesized, and one of these designed iminosugars was found to inhibit SOD1 fibrillation and break pre-formed fibrils. Docking and MD simulation studies indicated that this compound interacts with the key residue Arg69 of SOD1 through hydrogen bonding.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2023)
Article
Medicine, General & Internal
Teresa Cunha-Oliveira, Daniela Franco Silva, Luis Segura, Ines Baldeiras, Ricardo Marques, Tatiana Rosenstock, Paulo J. Oliveira, Filomena S. G. Silva
Summary: Distinct redox signatures were found in lymphoblasts from mutSOD1, undSOD1, and healthy controls, which can serve as therapeutic targets for ALS drug development. High heterogeneity in redox profiles between cohorts was observed, but clustering analysis successfully segregated healthy controls from ALS samples based on specific parameters. These findings provide valuable insights for understanding oxidative stress profiles in different forms of ALS and potential treatment strategies.
EUROPEAN JOURNAL OF CLINICAL INVESTIGATION
(2022)
Article
Clinical Neurology
Benjamin G. Trist, Sian Genoud, Stephane Roudeau, Alexander Rookyard, Amr Abdeen, Veronica Cottam, Dominic J. Hare, Melanie White, Jens Altvater, Jennifer A. Fifita, Alison Hogan, Natalie Grima, Ian P. Blair, Kai Kysenius, Peter J. Crouch, Asuncion Carmona, Yann Rufin, Stephane Claverol, Stijn Van Malderen, Gerald Falkenberg, David J. Paterson, Bradley Smith, Claire Troakes, Caroline Vance, Christopher E. Shaw, Safa Al-Sarraj, Stuart Cordwell, Glenda Halliday, Richard Ortega, Kay L. Double
Summary: This study examined the changes in SOD1 protein in post-mortem spinal cord tissues of ALS patients. The results showed mislocalization and accumulation of SOD1 protein in motor neurons of ALS patients, which was associated with instability and mismetallation of enzymatically active SOD1 dimers, as well as alterations to SOD1 post-translational modifications and molecular chaperones governing SOD1 maturation. These changes mostly occurred in regions of neurodegeneration and differentiated ALS patients from controls effectively.
Article
Neurosciences
Teresa Cunha-Oliveira, Marcelo Carvalho, Vilma Sardao, Elisabete Ferreiro, Debora Mena, Francisco B. Pereira, Fernanda Borges, Paulo J. Oliveira, Filomena S. G. Silva
Summary: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with mitochondrial alterations in lymphoblasts that may have diagnostic and therapeutic implications.
MOLECULAR NEUROBIOLOGY
(2022)
Article
Clinical Neurology
Karin M. Forsberg, Karin S. Graffmo, Erica Stenvall, Naima Tabikh, Stefan L. Marklund, Thomas Brannstrom, Peter M. Andersen
Summary: The D90A mutation in the SOD1 gene is associated with atypical features in amyotrophic lateral sclerosis, including slowly evolving motor symptoms, recessive heredity, and potential involvement of sensory, autonomic, and urinary bladder functions. This study reveals that neuropathological changes in patients with homozygous D90A mutation extend beyond the motor system to include cognitive and sensory cortical areas, but do not affect non-nervous organs.
ACTA NEUROPATHOLOGICA
(2023)
Article
Clinical Neurology
Delia Gagliardi, Paolo Ripellino, Megi Meneri, Roberto Del Bo, Sara Antognozzi, Giacomo Pietro Comi, Claudio Gobbi, Antonia Ratti, Nicola Ticozzi, Vincenzo Silani, Dario Ronchi, Stefania Corti
Summary: In this study, the authors provided a clinical and molecular description of a cohort of SOD1-ALS patients, revealing the heterogeneity in clinical and molecular characteristics of SOD1 mutations. The cohort exhibited variable expressivity, atypical presentations, and different modes of inheritance. With the availability of SOD1-directed antisense oligonucleotide for SOD1-ALS patients, prompt screening for SOD1 mutations in ALS patients is recommended.
FRONTIERS IN NEUROLOGY
(2023)
Article
Biochemistry & Molecular Biology
Nicholas G. M. Wells, Grant A. Tillinghast, Alison L. O'Neil, Colin A. Smith
Summary: SOD1 has been a key target in ALS research, but mutations have a significant impact on free energy changes during maturation, highlighting the need for state-specific therapeutic targeting. Many mutations show a disrupted allosteric network within SOD1, which may contribute to explaining SOD1-linked ALS disease.
Review
Cell Biology
Ilaria Martinelli, Elisabetta Zucchi, Cecilia Simonini, Giulia Gianferrari, Giovanna Zamboni, Marcello Pinti, Jessica Mandrioli
Summary: Although mutations in the SOD1 gene account for only a minority of ALS cases, the discovery of this gene has greatly expanded our understanding of the diverse pathogenic basis of ALS. This review focuses on cognitive impairment in SOD1-ALS patients and highlights the potential frailty of frontal lobe function in patients with different SOD1-ALS mutations. Thoroughly reviewing the reported mutations could contribute to a comprehensive genotype-phenotype correlation database for SOD1-ALS.
NEURAL REGENERATION RESEARCH
(2023)
Article
Clinical Neurology
Shlomit Ezer, Muhannad Daana, Julien H. Park, Shira Yanovsky-Dagan, Ulrika Nordstrom, Adily Basal, Simon Edvardson, Ann Saada, Markus Otto, Vardiella Meiner, Stefan L. Marklund, Peter Munch Andersen, Tamar Harel
Summary: Pathogenic variants in the SOD1 gene are associated with a severe motor-neurological syndrome in infants, characterized by global developmental delay and movement impairments. This study identified a homozygous loss-of-function variant in the SOD1 gene in an infant with severe neurological symptoms. Further analysis showed that this variant leads to instability and degeneration of the SOD1 protein. The study highlights the importance of specific valine residues in the SOD1 protein and suggests implications for future therapeutic research.
Article
Neurosciences
Cylia Rochat, Nathalie Bernard-Marissal, Emma Kaellstig, Sylvain Pradervand, Florence E. Perrin, Patrick Aebischer, Cedric Raoul, Bernard L. Schneider
Summary: This study evaluated the therapeutic potential of gene therapy targeting mutated SOD1 in mature astrocytes. The results showed that this treatment gradually restored neuromuscular connections and significantly improved neuromuscular function. Gene therapy in the spinal cord protected the most vulnerable fast-fatigable motor neurons, and specific muscle fiber types were also preserved.
Article
Chemistry, Multidisciplinary
Katelyn M. Baumer, Christopher D. Cook, Collin T. Zahler, Alexandra A. Beard, Zhijuan Chen, Jordan C. Koone, Chad M. Dashnaw, Raul A. Villacob, Touradj Solouki, John L. Wood, David R. Borchelt, Bryan F. Shaw
Summary: Repulsive electrostatic forces between prion-like proteins hinder aggregation, but compounds selectively boosting the negative charge of misfolded SOD1 were synthesized. These compounds showed slower aggregation of acetylated amyloid-SOD1 compared to unacetylated forms, and exhibited reactivity with other types of proteins.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Review
Chemistry, Medicinal
Kazumoto Shibuya, Ryo Otani, Yo-ichi Suzuki, Satoshi Kuwabara, Matthew C. Kiernan
Summary: Amyotrophic lateral sclerosis (ALS) is a devastating disease involving degeneration of upper and lower motor neurons. Riluzole and edaravone have been shown to slow disease progression in ALS by inhibiting glutamate and eliminating free radicals, respectively. Excessive activation of glutamate receptors generates free radicals, leading to excitotoxicity and neurodegeneration, which are key mechanisms in ALS.
Article
Chemistry, Medicinal
Bini Mathew, Pedro Ruiz, Shilpa Dutta, Jordan T. Entrekin, Sixue Zhang, Kaval D. Patel, Micah S. Simmons, Corinne E. Augelli-Szafran, Rita M. Cowell, Mark J. Suto
Summary: ALS is a rare neurodegenerative disease with unknown cause, characterized by the gradual degeneration of motor neurons. Mutations in SOD1 and SOD2 genes are associated with ALS. Research has shown that hybrid compounds of SRI-22819 and Ataluren may have improved therapeutic effects.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Neurosciences
Takashi Maruyama, Shogo Tanabe, Akiko Uyeda, Tatsunori Suzuki, Rieko Muramatsu
Summary: This study found that the concentration of free fatty acids (FFAs) in the blood of amyotrophic lateral sclerosis (ALS) patients decreased before disease onset. It was further discovered that oleic acid (OA) and linoleic acid (LA) could directly inhibit glutamate-induced oligodendrocyte cell death via free fatty acid receptor 1 (FFAR1). The authors concluded that the reduction of FFAs in the blood could serve as a pathogenic biomarker for early-stage ALS, and supplying FFAs could be a potential therapeutic approach to prevent oligodendrocyte cell death.
FRONTIERS IN CELLULAR NEUROSCIENCE
(2023)
Article
Clinical Neurology
Rubika Balendra, Ashley R. Jones, Ahmad Al Khleifat, Theresa Chiwera, Paul Wicks, Carolyn A. Young, Pamela J. Shaw, Martin R. Turner, P. Nigel Leigh, Ammar Al-Chalabi
Summary: ALS is a clinically heterogeneous disease and the King's clinical staging system has been proposed to aid in patient care, research, trial design and health economic analyses. This study validates the King's clinical staging system in four patient groups located in different regions and countries, demonstrating consistent results.
AMYOTROPHIC LATERAL SCLEROSIS AND FRONTOTEMPORAL DEGENERATION
(2023)
Article
Clinical Neurology
Ozlem Yildiz, Johannes Schroth, Timothy Tree, Martin R. Turner, Pamela J. Shaw, Sian M. Henson, Andrea Malaspina
Summary: In this study, researchers found that aging exacerbates neuroinflammation and older age is associated with a worse prognosis in ALS. They also discovered activation of cell senescence pathways and increase of proinflammatory cytokines in ALS patients. The findings suggest that lymphocyte senescence and memory state may play a central role in the progression of ALS.
NEUROLOGY-NEUROIMMUNOLOGY & NEUROINFLAMMATION
(2023)
Article
Biology
Tobias Moll, Valerie Odon, Calum Harvey, Mark O. Collins, Andrew Peden, John Franklin, Emily Graves, Jack N. G. Marshall, Cleide dos Santos Souza, Sai Zhang, Lydia Castelli, Guillaume Hautbergue, Mimoun Azzouz, David Gordon, Nevan Krogan, Laura Ferraiuolo, Michael P. Snyder, Pamela J. Shaw, Jan Rehwinkel, Johnathan Cooper-Knock
Summary: This study identifies a link between reduced expression of EXOSC2 and reduced SARS-CoV-2 replication. Increased expression of EXOSC2 is associated with higher risk of clinical COVID-19. The study also reveals interaction between the SARS-CoV-2 RNA polymerase and most of the human RNA exosome components.
LIFE SCIENCE ALLIANCE
(2023)
Article
Clinical Neurology
C. Toh, A. Keslake, T. Payne, A. Onwuegbuzie, J. Harding, K. Baster, N. Hoggard, P. J. Shaw, I. D. Wilkinson, T. M. Jenkins
Summary: This study analyzed MRI data of the brain and cervical spinal cord to investigate pathophysiological hypotheses in vivo. A cranio-caudal step-change in MND patients was observed, which requires further investigation in larger cohorts.
JOURNAL OF NEUROLOGY
(2023)
Article
Spectroscopy
James J. P. Alix, Maria Plesia, Chloe N. Schooling, Alexander P. Dudgeon, Catherine A. Kendall, Visakan Kadirkamanathan, Christopher J. McDermott, Grainne S. Gorman, Robert W. Taylor, Richard J. Mead, Pamela J. Shaw, John C. Day
Summary: Raman spectroscopy shows promise as a biomarker for neuromuscular diseases. Challenges include sensitivity to instrument configurations, translation across tissues, and development of analytics for disease identification. Nonnegative matrix factorisation (NMF) was used to analyse Raman spectra from different clinical and preclinical settings, accurately identifying disease states. NMF decomposition enhances the potential of Raman spectroscopy for studying fatal neuromuscular diseases.
JOURNAL OF RAMAN SPECTROSCOPY
(2023)
Review
Biotechnology & Applied Microbiology
Richard J. Mead, Ning Shan, H. Joseph Reiser, Fiona Marshall, Pamela J. Shaw
Summary: Amyotrophic lateral sclerosis (ALS) is a devastating disease with degeneration of motor neurons. Despite the challenges, ALS has seen progress in the development of disease-modifying therapies. Significant advancements have been made in ALS research and novel therapeutic approaches are being applied to address unmet medical needs. This review discusses how advanced knowledge and new approaches can lead to effective translation of therapies for ALS and potentially impact drug discovery for neurodegenerative disorders.
NATURE REVIEWS DRUG DISCOVERY
(2023)
Review
Clinical Neurology
Ilaria Giovannelli, Adrian Higginbottom, Janine Kirby, Mimoun Azzouz, Pamela J. Shaw
Summary: Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterized by the progressive loss of motor neurons. Recent advances in genetic therapy offer new opportunities for treating ALS, although there are still challenges to overcome.
NATURE REVIEWS NEUROLOGY
(2023)
Review
Clinical Neurology
Laura Chapman, Johnathan Cooper-Knock, Pamela J. Shaw
Summary: Chapman et al. reviewed published evidence on the link between strenuous physical activity and the development of ALS. The consensus supports physical activity as a risk factor for ALS, with genetic susceptibility also playing a role.
Article
Neurosciences
Zhongbo Chen, Regina H. Reynolds, Antonio F. Pardinas, Sarah A. Gagliano Taliun, Wouter van Rheenen, Kuang Lin, Aleksey Shatunov, Emil K. Gustavsson, Isabella Fogh, Ashley R. Jones, Wim Robberecht, Philippe Corcia, Adriano Chio, Pamela J. Shaw, Karen E. Morrison, Jan H. Veldink, Leonard H. van den Berg, Christopher E. Shaw, John F. Powell, Vincenzo Silani, John A. Hardy, Henry Houlden, Michael J. Owen, Martin R. Turner, Mina Ryten, Ammar Al-Chalabi
Summary: This study found that Neanderthal DNA introgression does not contribute to the genetic risk of neurodegenerative disorders in anatomically-modern humans. Additionally, there is no evidence to support the idea that common variants associated with these disorders are maintained by natural selection. These findings provide valuable insights into the origins of neurodegenerative diseases and address longstanding debates.
NEUROBIOLOGY OF DISEASE
(2023)
Article
Cell Biology
Lydia M. Castelli, Ya-Hui Lin, Alvaro Sanchez-Martinez, Aytac Gul, Kamallia Mohd Imran, Adrian Higginbottom, Santosh Kumar Upadhyay, Nora M. Markus, Raquel Rua Martins, Johnathan Cooper-Knock, Claire Montmasson, Rebecca Cohen, Amy Walton, Claudia S. Bauer, Kurt J. De Vos, Richard J. Mead, Mimoun Azzouz, Cyril Dominguez, Laura Ferraiuolo, Pamela J. Shaw, Alexander J. Whitworth, Guillaume M. Hautbergue
Summary: Hexanucleotide repeat expansions in C9ORF72 are a common genetic cause of familial ALS and FTD. These expansions result in the translation of neurotoxic DPRs that contribute to neurodegeneration. A cell-penetrant peptide was found to block the export and translation of C9ORF72-repeat transcripts and toxic DPRs, leading to improved survival of ALS motor neurons and decreased DPR expression in animal models. Disrupting DPR production may be a potential strategy to ameliorate neurodegeneration in ALS/FTD.
SCIENCE TRANSLATIONAL MEDICINE
(2023)
Article
Neurosciences
Brett N. Adey, Johnathan Cooper-Knock, Ahmad Al Khleifat, Isabella Fogh, Philip van Damme, Philippe Corcia, Philippe Couratier, Orla Hardiman, Russell McLaughlin, Marc Gotkine, Vivian Drory, Vincenzo Silani, Nicola Ticozzi, Jan H. Veldink, Leonard H. van den Berg, Mamede de Carvalho, Susana Pinto, Jesus S. Mora S. Pardina, Monica Povedano Panades, Peter M. Andersen, Markus Weber, Nazli A. Basak, Christopher E. Shaw, Pamela J. Shaw, Karen E. Morrison, John E. Landers, Jonathan D. Glass, Patrick Vourc'h, Richard J. B. Dobson, Gerome Breen, Ammar Al-Chalabi, Ashley R. Jones, Alfredo Iacoangeli
Summary: This study explores the relationship between CAV1/2 genes and ALS. The expression of CAV1 and CAV2 genes is found to be higher in ALS patients compared to controls, and carriers of CAV1/2 enhancer mutations show improved survival and slower progression of the disease.
FRONTIERS IN CELLULAR NEUROSCIENCE
(2023)
Article
Clinical Neurology
James J. P. Alix, Maria Plesia, Pamela J. Shaw, Richard J. Mead, John C. C. Day
Summary: Optical EMG, combining EMG and Raman spectroscopy, can provide both electrophysiological and molecular data during a single needle insertion, offering potential diagnostic information for neuromuscular diseases. The experimental results demonstrate that optical EMG can detect specific muscle activation and identify molecular composition differences in diseased muscle through Raman spectra.
Correction
Biochemistry & Molecular Biology
Siew Chin Chan, Chih-Wei Tung, Chia-Wei Lin, Yun-Shiuan Tung, Po-Min Wu, Pei-Hsun Cheng, Chuan-Mu Chen, Shang-Hsun Yang
FREE RADICAL BIOLOGY AND MEDICINE
(2024)
Article
Biochemistry & Molecular Biology
Suyuan Liu, Meiling Tan, Jiangxue Cai, Chenxuan Li, Miaoxin Yang, Xiaoxiao Sun, Bin He
Summary: This study reveals that the antibiotic doxycycline effectively inhibits NLRP3 inflammasome activation by targeting mitochondrial translation and mtDNA synthesis, offering potential for the treatment of NLRP3-related diseases.
FREE RADICAL BIOLOGY AND MEDICINE
(2024)
Article
Biochemistry & Molecular Biology
Hao Liu, Nana Li, Ge Kuang, Xia Gong, Ting Wang, Jun Hu, Hui Du, Minxuan Zhong, Jiashi Guo, Yao Xie, Yang Xiang, Shengwang Wu, Yiling Yuan, Xinru Yin, Jingyuan Wan, Ke Li
Summary: Protectin D1 (PTD1) improves hepatic steatosis, inflammation and fibrosis in a NASH mouse model by inhibiting the activation of TLR4 downstream signaling pathway, possibly through upregulation of IRAK-M expression, suggesting a potential new treatment for NASH.
FREE RADICAL BIOLOGY AND MEDICINE
(2024)