Review
Clinical Neurology
Sean W. Willemse, Michael A. van Es
Summary: The purpose of this review is to outline how advances in genetic studies of ALS are being translated into novel therapeutic strategies. Recent findings show that specific therapeutic targeting of mutant genes, such as antisense oligonucleotide therapy, have led to successful gene therapy for SOD1-ALS and multiple other gene-targeted trials are underway.
CURRENT OPINION IN NEUROLOGY
(2023)
Review
Clinical Neurology
Philippe Corcia, Christian Lunetta, Patrick Vourc'h, Pierre-Francois Pradat, Helene Blasco
Summary: This article reviews the progress in the diagnosis, monitoring, and treatment of amyotrophic lateral sclerosis (ALS). Despite the difficulty in diagnosing and the lack of a cure for ALS, there is evidence to suggest that an optimistic view of ALS management in the coming years is now realistic.
EUROPEAN JOURNAL OF NEUROLOGY
(2023)
Review
Neurosciences
Hui Wang, LiPing Guan, Min Deng
Summary: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the degeneration of motor neurons. The causes of ALS are not fully understood but genetic factors play a role in about 10% of cases. Recent studies have identified over 40 ALS genes, which contribute to a better understanding of the disease and the development of potential treatments.
FRONTIERS IN NEUROSCIENCE
(2023)
Article
Biochemistry & Molecular Biology
Jose R. Monteiro Neto, Gabriela D. Ribeiro, Rayne S. S. Magalhaes, Cristian Follmer, Tiago F. Outeiro, Elis C. A. Eleutherio
Summary: This study found a relationship between the formation of methylglyoxal (MGO) and the degeneration of motor neurons in Amyotrophic Lateral Sclerosis (ALS). The accumulation of MGO led to the aggregation of human SOD1WT (hSOD1WT), decreased activity, and reduced cell viability. Additionally, MGO treatment increased the presence of hSOD1WT in stress granules. These findings suggest that glycation may play a significant role in the pathologies of hSOD1WT and TDP-43 in sporadic ALS.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
(2023)
Review
Biochemistry & Molecular Biology
Sophie Layalle, Laetitia They, Sarah Ourghani, Cedric Raoul, Laurent Soustelle
Summary: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the degeneration of motoneurons. Fruit flies have emerged as a versatile model for studying ALS, providing insights into cellular mechanisms and potential therapeutic targets for future treatments. Research on fruit fly ALS models has revealed novel pathogenic mechanisms and identified disease-modifying genes.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Clinical Neurology
Simon Witzel, Kristina Mayer, Patrick Oeckl
Summary: Amyotrophic lateral sclerosis (ALS) is an incurable and devastating neurodegenerative disease with limited treatment options. However, there is promising progress in potential treatments currently being tested in clinical trials. This review discusses recent advances in ALS biomarker research and applications, as well as future directions and needs.
CURRENT OPINION IN NEUROLOGY
(2022)
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
Neurosciences
Rebecca Stevenson, Evgeniia Samokhina, Armaan Mangat, Ilaria Rossetti, Sushmitha S. Purushotham, Chandra S. Malladi, John W. Morley, Yossi Buskila
Summary: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the progressive loss of motor neurons. Recent studies have shown that astrocytes, a type of glial cells, also contribute to the onset and progression of ALS. This study investigates the role of astrocytes in maintaining K+ homeostasis in the brain and demonstrates region-specific alterations in K+ clearance rate in an ALS mouse model. The findings suggest that impaired astrocytic function may contribute to the vulnerability of motor neurons in ALS.
Article
Medicine, Research & Experimental
Takayuki Kondo, Ikuyo Inoue, Kazuhiro Umeyama, Masahito Watanabe, Hitomi Matsunari, Ayuko Uchikura, Kazuaki Nakano, Kayoko Tsukita, Keiko Imamura, Hiroshi Nagashima, Haruhisa Inoue
Summary: In this study, a pig model of human mutant SOD1-mediated familial ALS was generated by delivering a genetic construct into porcine zygotes using intra-cytoplasmic sperm injection-mediated gene transfer. The established ALS pig model exhibited initial abnormalities of motor neurons and accumulated misfolded SOD1. This ALS pig model, with a body size similar to that of human beings, could be utilized for cell and gene therapy platforms in preclinical translational research.
LABORATORY INVESTIGATION
(2023)
Article
Clinical Neurology
Kelly G. Gwathmey, Philippe Corcia, Chris J. McDermott, Angela Genge, Stefan Sennfalt, Mamede de Carvalho, Caroline Ingre
Summary: ALS is a fatal neurodegenerative disease with a long delay in diagnosis. This delay is influenced by lack of recognition and misdiagnosis by general practitioners, as well as patient factors such as illness behavior and site of symptom onset.
EUROPEAN JOURNAL OF NEUROLOGY
(2023)
Article
Pharmacology & Pharmacy
Silvia Scaricamazza, Illari Salvatori, Susanna Amadio, Valentina Nesci, Alessio Torcinaro, Giacomo Giacovazzo, Aniello Primiano, Michela Gloriani, Niccolo Candelise, Luisa Pieroni, Jean-Philippe Loeffler, Frederique Rene, Cyril Quessada, Tesfaye W. Tefera, Hao Wang, Frederik J. Steyn, Shyuan T. Ngo, Gabriella Dobrowolny, Elisa Lepore, Andrea Urbani, Antonio Musaro, Cinzia Volonte, Elisabetta Ferraro, Roberto Coccurello, Cristiana Valle, Alberto Ferri
Summary: The therapeutic potential of the multi-target drug trimetazidine was evaluated in SOD1(G93A) mice. The results showed that trimetazidine delayed disease progression, improved motor function and metabolism, and increased overall survival of the mice.
BRITISH JOURNAL OF PHARMACOLOGY
(2022)
Review
Endocrinology & Metabolism
Nader Akbari Dilmaghani, Bashdar Mahmud Hussen, Saeedeh Nateghinia, Mohammad Taheri, Soudeh Ghafouri-Fard
Summary: ALS, a deadly motor neuron disease, is classified into familial and sporadic types, with genetic risk factors not fully identified in sporadic cases. Studies have shown dysregulation of multiple miRNAs in ALS patients' serum samples and brain tissues, some of which may serve as potential biomarkers for sporadic ALS.
METABOLIC BRAIN DISEASE
(2021)
Article
Pharmacology & Pharmacy
Hiroki Tanaka, Nae Takata, Yu Sakurai, Tokuyuki Yoshida, Takao Inoue, Shinya Tamagawa, Yuta Nakai, Kota Tange, Hiroki Yoshioka, Masatoshi Maeki, Manabu Tokeshi, Hidetaka Akita
Summary: This study investigated the optimal lipid composition of LNPs for the delivery of siRNA and ASO, finding that the optimal compositions for siRNA and ASO were different and differed from those reported for mRNA in previous studies. The key processes for successful delivery of mRNA, siRNA, and ASO were identified as extracellular stability, endosomal escape, and cellular uptake, respectively, indicating the importance of optimizing LNP lipid compositions based on the type of nucleic acids being delivered.
Article
Neurosciences
Albert J. B. Lee, Tyler E. E. Kittel, Renaid B. B. Kim, Thao-Nguyen Bach, Tian Zhang, Cassie S. S. Mitchell
Summary: The study aimed to determine the most beneficial pathophysiological treatment targets for ALS. The results showed that treatments targeting inflammation were best at delaying disease onset, oxidative stress treatments significantly prolonged survival, and excitability treatments improved overall health status. The best pathophysiological treatment category varied with disease progression and combination treatments targeting multiple categories performed better than monotherapies at end-stage.
FRONTIERS IN NEUROSCIENCE
(2023)
Article
Neurosciences
Cassandra N. Dennys, Florence Roussel, Rochelle Rodrigo, Xiaojin Zhang, Andrea Sierra Delgado, Annalisa Hartlaub, Asya Saelim-Ector, Will Ray, Sarah Heintzman, Ashley Fox, Stephen J. Kolb, Joseph Beckman, Maria Clara Franco, Kathrin Meyer
Summary: Patient diversity and unknown disease cause pose challenges for drug development and clinical trial design in ALS. Reprogramming patient fibroblasts to neuronal progenitor cells can generate disease relevant cell types for compound testing. CuATSM, currently in clinical trial for ALS, showed a differential effect on neuronal survival in co-culture assays. Elevated mitochondrial respiration was observed in all CuATSM-responders, suggesting a potential metabolic mechanism for CuATSM's therapeutic effects.
Article
Chemistry, Multidisciplinary
Jiefei Wang, Yisheng Liu, Marco Morsch, Yiqing Lu, Ping Shangguan, Lulu Han, Zhongjie Wang, Xiaoyu Chen, Chenhui Song, Shunjie Liu, Bingyang Shi, Ben Zhong Tang
Summary: This study presents the development of brain-targeted near-infrared IIb aggregation-induced-emission nanoparticles via rational design, achieving a balance between fluorescence imaging and photothermal therapy demands. The nanoparticles, grafted with ApoE peptide, demonstrate efficient BBB traversal and enhanced survival in mice with orthotopic GBM, highlighting a new theranostic approach for the treatment of GBM.
ADVANCED MATERIALS
(2022)
Article
Chemistry, Multidisciplinary
Wenya He, Xiaozhe Li, Marco Morsch, Muhammad Ismail, Yanjie Liu, Fawad Ur Rehman, Dongya Zhang, Yibin Wang, Meng Zheng, Roger Chung, Yan Zou, Bingyang Shi
Summary: In this study, the researchers discovered that the Mcl-1-specific inhibitor A12 synergizes with ABT to induce potent cell apoptosis in GBM. They also developed a biomimetic nanomedicine that can effectively deliver ABT and A12 to the brain, exhibiting good biocompatibility and efficient blood-brain barrier penetration. This nanomedicine effectively suppressed tumor growth and prolonged the survival time of mice with GBM xenografts without inducing adverse effects.
Article
Neurosciences
Jeremy S. Lum, Tracey Berg, Christen G. Chisholm, Michele Vendruscolo, Justin J. Yerbury
Summary: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor neuron loss and paralysis. Synaptic alterations and protein homeostasis disturbances in the motor neuron presynaptic terminal may contribute to the synaptic dysfunction observed in ALS.
NEUROSCIENCE LETTERS
(2022)
Article
Pharmacology & Pharmacy
Michael Lau, Benjamin Sealy, Valery Combes, Marco Morsch, Alfonso E. Garcia-Bennett
Summary: The integrity of the blood-brain barrier (BBB) is crucial for the health of the nervous system. In this study, we found that loading the compound probucol within mesoporous silica particles (MSP) can enhance its antioxidant effects, thereby protecting the function and integrity of brain endothelial cells. Through in vitro and in vivo experiments using zebrafish models, we demonstrated that probucol-loaded MSPs can significantly reduce cellular damage caused by oxidative stress and inflammation, and decrease the permeability of the BBB.
Article
Biochemical Research Methods
Adrianne L. L. Jenner, Wayne Kelly, Michael Dallaston, Robyn Araujo, Isobelle Parfitt, Dominic Steinitz, Pantea Pooladvand, Peter S. S. Kim, Samantha J. J. Wade, Kara L. L. Vine
Summary: Pancreatic cancer has a poor prognosis due to limited efficacy of systemic chemotherapy. Sustained-release devices have been proposed as a solution to this problem. A mathematical model was developed to investigate the efficacy of these devices, allowing for better understanding of optimal treatment.
PLOS COMPUTATIONAL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Natalie E. Farrawell, Monique Bax, Luke McAlary, Jessie McKenna, Simon Maksour, Dzung Do-Ha, Stephanie L. Rayner, Ian P. Blair, Roger S. Chung, Justin J. Yerbury, Lezanne Ooi, Darren N. Saunders
Summary: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders characterized by the accumulation of ubiquitinated protein inclusions in motor neurons. A pathogenic variant in the CCNF gene was found to disrupt ubiquitin homeostasis, leading to dysfunction in the ubiquitin-proteasome system (UPS) and contributing to the development of CCNF-associated ALS/FTD.
HUMAN MOLECULAR GENETICS
(2023)
Article
Biochemistry & Molecular Biology
Jennilee M. Davidson, Stephanie L. Rayner, Sidong Liu, Flora Cheng, Antonio Di Ieva, Roger S. Chung, Albert Lee
Summary: Proteomics has great potential in studying the molecular regulation of the human brain. This study compared the efficiency of two different protein-extraction buffers on formalin-fixed human brains, and found that a lysis buffer containing TrisHCl, SDS, SDC, and Triton X-100 had superior protein extraction performance. The analysis also revealed differential enrichment of proteins in different brain regions, indicating commonalities in the molecular regulation of neuroanatomically-linked brain functions. Overall, the study developed an optimized method for protein extraction from formalin-fixed human brain tissue and demonstrated its suitability for rapid and routine analysis of molecular signaling pathways in the human brain.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Rowan A. W. Radford, Stephanie L. Rayner, Paulina Szwaja, Marco Morsch, Flora Cheng, Tianyi Zhu, Jocelyn Widagdo, Victor Anggono, Dean L. Pountney, Roger Chung, Albert Lee
Summary: Progressive supranuclear palsy (PSP) is a neurodegenerative disease characterized by the presence of insoluble phosphorylated-Tau (p-Tau) in neurons and glia. In this study, a proteomic approach using antibody-mediated biotinylation and mass spectrometry (MS) was used to identify proteins near p-Tau inclusions in PSP. The results showed the presence of previously identified interacting proteins of Tau and known modifiers of Tau aggregation, as well as 19 novel proteins associated with Tau. Additionally, the study found proteins related to neurological disorders and pathways involved in various cellular processes.
JOURNAL OF NEUROCHEMISTRY
(2023)
Review
Chemistry, Medicinal
Jessica Merjane, Roger Chung, Rickie Patani, Leszek Lisowski
Summary: Despite the mysterious etiology, differentiated treatments are required for ALS to address both familial and sporadic cases. Targeting mechanisms of defective protein homeostasis and RNA processing, as well as exploring the use of gene therapy through adeno-associated virus (AAV) for gene delivery to the CNS, might provide potential therapeutic interventions. Overall, there is a strong need for disease modifying treatments for ALS that can effectively treat the full spectrum of cases.
MEDICINAL RESEARCH REVIEWS
(2023)
Article
Neurosciences
Jennilee M. Davidson, Sharlynn S. L. Wu, Stephanie L. Rayner, Flora Cheng, Kimberley Duncan, Carlo Russo, Michelle Newbery, Kunjie Ding, Natalie M. Scherer, Rachelle Balez, Alberto Garcia-Redondo, Alberto Rabano, Livia Rosa-Fernandes, Lezanne Ooi, Kelly L. Williams, Marco Morsch, Ian P. Blair, Antonio Di Ieva, Shu Yang, Roger S. Chung, Albert Lee
Summary: This study reveals the role of cyclin F in regulating substrate solubility and its contribution to the pathogenesis of ALS and FTD. The ALS and FTD-associated protein p62 is identified as a substrate of cyclin F, and its aggregation is promoted by cyclin F expression. Mutations in cyclin F result in dysregulated p62 solubility and formation of p62 foci, which are associated with ALS and FTD pathogenesis.
MOLECULAR NEUROBIOLOGY
(2023)
Article
Medicine, Research & Experimental
Ashna A. Kumar, Kara L. Vine, Marie Ranson
Summary: The abnormal proteinase spectrum in the tumor microenvironment plays a crucial role in cancer progression. The overexpression of urokinase plasminogen activator (uPA) and its associated cell-surface receptor (uPAR) in tumors compared to normal tissue is strongly associated with worse clinical and pathological features as well as poorer patient survival in various types of cancer. This is due to the activation of proteolytic processes that lead to invasion, migration, and metastasis through the degradation of the extracellular matrix. Targeting uPA has been regarded as a promising anticancer strategy, but the limited bioavailability of uPA-selective small-molecule inhibitors has hindered their clinical progress. The use of nanodelivery systems offers a potential solution to enhance the pharmacokinetic profile of uPA inhibitors, improve their bioavailability, and enable targeted delivery to tumor tissue, thereby overcoming the challenges associated with conventional uPA inhibitors.
MOLECULAR PHARMACEUTICS
(2023)
Editorial Material
Medicine, Research & Experimental
Orlagh M. Feeney, Christopher J. H. Porter, Kara L. Vine
MOLECULAR PHARMACEUTICS
(2023)
Article
Clinical Neurology
Annika van Hummel, Miheer Sabale, Magdalena Przybyla, Julia van der Hoven, Gabriella Chan, Astrid F. Feiten, Roger S. Chung, Lars M. Ittner, Yazi D. Ke
Summary: This study developed the first mouse models expressing wild-type and mutant human CCNF genes to replicate the key clinical and neuropathological features of ALS and FTD linked to CCNF disease variants. The results showed that these mice exhibited behavioral abnormalities similar to FTD patients, as well as memory deficits. Furthermore, the study found altered CCNF-mediated pathways and abnormal TDP-43 neuropathology, which are key hallmarks of FTD/ALS pathology.
NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY
(2023)
Review
Cell Biology
Afshin Babazadeh, Stephanie L. Rayner, Albert Lee, Roger S. Chung
Summary: A common feature of adult-onset neurodegenerative diseases is the presence of specific pathological protein accumulations. Restoring protein homeostasis of these accumulations may represent a potential therapeutic strategy. This review discusses the mechanisms leading to disrupted protein homeostasis and explores small molecule-based therapies for modulating these mechanisms.
AGEING RESEARCH REVIEWS
(2023)
Article
Biochemistry & Molecular Biology
Brandon Mahan, Theo Tacail, Jamie Lewis, Tim Elliott, Mette Habekost, Simon Turner, Roger Chung, Frederic Moynier
Summary: Natural stable metal isotopes have shown potential in differentiating healthy and diseased brain states. Alzheimer's disease brains expel potassium, which is accompanied by increased serum potassium levels. Heavy potassium isotope enrichment is observed in the regions of amyloid beta accumulation, which correlates with potassium depletion. The composition of potassium isotopes in the brain differs from that in serum, suggesting the generation of an early Alzheimer's disease biomarker.
