Article
Neurosciences
Emily E. Handley, Laura A. Reale, Jyoti A. Chuckowree, Marcus S. Dyer, Grace L. Barnett, Courtney M. Clark, William Bennett, Tracey C. Dickson, Catherine A. Blizzard
Summary: Estrogen plays a significant role in mitigating disease progression and pathogenesis in ALS, by influencing spine density and plasticity, resulting in improved disease severity and outcomes.
MOLECULAR NEUROBIOLOGY
(2022)
Article
Clinical Neurology
Hadjara Sidibe, Yousra Khalfallah, Shangxi Xiao, Nicolas B. Gomez, Hana Fakim, Elizabeth M. H. Tank, Genevieve Di Tomasso, Eric Bareke, Anais Aulas, Paul M. McKeever, Ze'ev Melamed, Laurie Destroimaisons, Jade-Emmanuelle Deshaies, Lorne Zinman, J. Alex Parker, Pascale Legault, Martine Tetreault, Sami J. Barmada, Janice Robertson, Christine Vande Velde
Summary: The study reveals that TDP-43 stabilizes G3BP1 transcripts, nuclear TDP-43 depletion is sufficient to reduce G3BP1 protein levels, and G3BP1 transcripts are reduced in neurons of ALS/FTD patients with TDP-43 cytoplasmic inclusions/nuclear depletion. These findings suggest that loss of function of TDP-43 and G3BP1 may contribute to ALS/FTD pathogenesis.
Article
Biochemistry & Molecular Biology
Giada Zanini, Valentina Selleri, Milena Nasi, Anna De Gaetano, Ilaria Martinelli, Giulia Gianferrari, Francesco Demetrio Lofaro, Federica Boraldi, Jessica Mandrioli, Marcello Pinti
Summary: This study reports the clinical and biological features of an ALS patient with pA382T mutation in TPD-43 protein. The mutation leads to significant alterations in neuronal proteome, particularly impacting mitochondrial metabolic pathways and the endoplasmic reticulum. The findings suggest that mitochondrial dysfunction and misplacement of mitochondrial DNA may be mechanisms contributing to ALS caused by this mutation.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Clinical Neurology
Yuting Ren, Siyuan Li, Siyu Chen, Xiaosun Sun, Fei Yang, Hongfen Wang, Mao Li, Fang Cui, Xusheng Huang
Summary: The levels of plasma TDP-43 and pTDP-43 were significantly higher in ALS patients compared to healthy controls, with plasma TDP-43 showing high sensitivity and specificity in differentiating between the two groups and indicating disease progression.
FRONTIERS IN NEUROLOGY
(2021)
Article
Neurosciences
Maize C. Cao, Brigid Ryan, Jane Wu, Maurice A. Curtis, Richard L. M. Faull, Mike Dragunow, Emma L. Scotter
Summary: TDP-43 dysfunction is a molecular characteristic of ALS and FTD. It leads to the loss of normal nuclear function, resulting in impaired RNA regulation and the emergence of cryptic exons. Cryptic exons and differential exon usage are promising markers of TDP-43 dysfunction in ALS/FTD and provide insights into neurodegenerative pathways.
NEUROBIOLOGY OF DISEASE
(2023)
Article
Biochemistry & Molecular Biology
Greta Grassmann, Mattia Miotto, Lorenzo Di Rienzo, Federico Salaris, Beatrice Silvestri, Elsa Zacco, Alessandro Rosa, Gian Gaetano Tartaglia, Giancarlo Ruocco, Edoardo Milanetti
Summary: This article investigates the protein aggregation process in ALS, providing a computational model of interaction based on the evaluation of shape complementarity at the molecular interfaces. The study proposes and assesses possible association mechanisms between CTFs, and performs molecular docking and additional MD simulations to propose possible complexes and evaluate their stability, focusing on high shape complementarity and involvement of beta 3 and beta 5 strands at the interfaces.
Review
Neurosciences
Sarah Lepine, Maria Jose Castellanos-Montiel, Thomas Martin Durcan
Summary: The abnormal synaptic function of TDP-43 is closely related to NMJ disruption in ALS, and it may exert its effects by influencing molecular mechanisms within motor neurons, skeletal muscles, and glial cells.
TRANSLATIONAL NEURODEGENERATION
(2022)
Article
Neurosciences
Rachel H. Tan, Heather McCann, Claire E. Shepherd, Monica Pinkerton, Srestha Mazumder, Emma M. Devenney, Gabrielle L. Adler, Dominic B. Rowe, Jillian Kril, Glenda M. Halliday, Matthew C. Kiernan
Summary: Despite the presence of significant cortical pTDP-43 inclusions of heterogeneous morphologies in patients diagnosed with ALS, pathological subclassification is routinely performed in the minority of patients with concomitant FTD. In this study, three distinct ALS-TDP subtypes were identified based on the presence, morphology, and composition of pTDP-43 pathology. These subtypes show different levels of pTDP-43 burden and are associated with different neuropathological changes and cognitive scores.
ACTA NEUROPATHOLOGICA COMMUNICATIONS
(2023)
Article
Immunology
Swetha Ramachandran, Veselin Grozdanov, Bianca Leins, Katharina Kandler, Simon Witzel, Medhanie Mulaw, Albert C. Ludolph, Jochen H. Weishaupt, Karin M. Danzer
Summary: This study found that the activation of T cells is increased in patients with ALS, but the antigen that leads to their activation has not been identified. The study also found that ALS patients have lower levels of T cell activation to TDP-43 and control stimuli compared to healthy individuals.
FRONTIERS IN IMMUNOLOGY
(2023)
Article
Geriatrics & Gerontology
Zhe Long, Muireann Irish, John R. Hodges, Glenda Halliday, Olivier Piguet, James R. Burrell
Summary: Clinical and pathological heterogeneity is common in patients with frontotemporal lobar degeneration (FTLD) pathology. Characteristics that differentiate between FTLD-TDP and FTLD-tau, as well as different subtypes within FTLD-TDP, were investigated. Amyotrophic lateral sclerosis features were highly specific for FTLD-TDP, which showed greater atrophy than FTLD-tau. TDP-43 subtyping may have more clinical utility in distinguishing different profiles within FTLD-TDP.
NEUROBIOLOGY OF AGING
(2021)
Article
Biochemistry & Molecular Biology
Donya Pakravan, Emiel Michiels, Anna Bratek-Skicki, Mathias De Decker, Joris Van Lindt, David Alsteens, Sylvie Derclaye, Philip Van Damme, Joost Schymkowitz, Frederic Rousseau, Peter Tompa, Ludo van den Bosch
Summary: This study investigated how phase separation affects the aggregation of TDP-43 protein, finding that liquid-liquid phase separation (LLPS) promotes spontaneous aggregation but hinders seeded aggregation. Analysis of various conditions using buffers showed that stabilizing hydrophobic interactions are more important than destabilizing electrostatic forces. RNA was found to affect the cooperativity between LLPS and aggregation in a reentrant manner.
Article
Neurosciences
Marcus S. Dyer, Adele Woodhouse, Catherine A. Blizzard
Summary: ALS is characterized by the destruction of upper- and lower motor neurons, with the mislocalization of TDP-43 protein potentially causing hyperexcitability of upper motor neurons in ALS patients. TDP-43 mislocalization is found to impact the formation and durability of excitatory synapses, leading to network dysfunction in ALS.
Article
Neurosciences
Minggang Fang, Sara K. Deibler, Alissa L. Nana, Sarat C. Vatsavayai, Shahid Banday, You Zhou, Sandra Almeida, Alexandra Weiss, Robert H. Brown, William W. Seeley, Fen-Biao Gao, Michael R. Green
Summary: Loss of nuclear TDP-43 function contributes to increased DNA damage in ALS and FTD patients due to defects in DNA repair pathways.
FRONTIERS IN NEUROSCIENCE
(2023)
Article
Neurosciences
Molly E. V. Swanson, Miran Mrkela, Helen C. C. Murray, Maize C. C. Cao, Clinton Turner, Maurice A. A. Curtis, Richard L. M. Faull, Adam K. K. Walker, Emma L. L. Scotter
Summary: The activation of microglia in ALS is associated with TDP-43 aggregation, with phagocytic state in early-stage disease and dysfunctional state in end-stage disease. These findings enhance our understanding of microglial phenotypes and function in ALS.
ACTA NEUROPATHOLOGICA COMMUNICATIONS
(2023)
Article
Clinical Neurology
Fumiaki Mori, Hina Yasui, Yasuo Miki, Tomoya Kon, Akira Arai, Hidekachi Kurotaki, Masahiko Tomiyama, Koichi Wakabayashi
Summary: This study found that TDP-43 and SGs colocalize at the early stage of TDP-43 aggregation, suggesting the involvement of SGs in the formation of TDP-43 inclusions.
Article
Clinical Neurology
Jeryn Chang, Thomas B. Shaw, Cory J. Holdom, Pamela A. McCombe, Robert D. Henderson, Jurgen Fripp, Markus Barth, Christine C. Guo, Shyuan T. Ngo, Frederik J. Steyn
Summary: This study found that lower hypothalamic volume is associated with lower and higher BMI in ALS patients, unlike AD patients and controls. Hypothalamic volume is not related to loss of appetite or hypermetabolism. In ALS patients, lower hypothalamic volume with lower BMI is associated with weight loss and earlier death.
EUROPEAN JOURNAL OF NEUROLOGY
(2023)
Review
Endocrinology & Metabolism
Tanya S. McDonald, Titaya Lerskiatiphanich, Trent M. Woodruff, Pamela A. McCombe, John D. Lee
Summary: Neurodegeneration refers to the progressive loss of neurons in disorders like Alzheimer's, Huntington's, and Parkinson's disease. Energy metabolism disturbances and alterations are common features in the onset and progression of these diseases. Understanding these metabolic changes could lead to improved treatment options for neurodegenerative disorders.
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
(2023)
Article
Biochemistry & Molecular Biology
Dai Shi, Jaime K. Y. Wong, Kaichuan Zhu, Peter G. Noakes, Gerhard Rammes
Summary: It has been suggested that inhalational anesthetics like isoflurane may contribute to the development of Alzheimer's disease, while xenon exhibits neuroprotective properties. The phagocytic receptor MEGF10 has been found to assist in the elimination of synapses by astrocytes. This study investigated the interaction between beta-amyloid peptide 1-42, isoflurane, xenon, and MEGF10-dependent synapse elimination.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Clinical Neurology
Cory J. Holdom, Jordi W. J. van Unnik, Ruben P. A. van Eijk, Leonard H. van den Berg, Robert D. Henderson, Shyuan T. Ngo, Frederik J. Steyn
Summary: This study examined the use of wrist and hip accelerometers to measure activity levels in patients with Motor Neuron Disease (MND) compared to controls. The results showed that wrist-based measurements were more variable and had differing sensitivity to specific functional outcomes compared to hip-based measurements. Careful selection of measurement devices and analysis methods is necessary for at-home monitoring of disease progression in patients with MND.
JOURNAL OF NEUROLOGY
(2023)
Article
Physiology
Matthew J. Fogarty, Gary C. Sieck
Summary: Using a rat model, this study found that with aging, there is a loss of larger phrenic motor neurons and motor fibers, as well as demyelination of the larger phrenic alpha motor axons. These changes may contribute to the reduced muscle strength of the diaphragm with age.
PHYSIOLOGICAL REPORTS
(2023)
Review
Clinical Neurology
Jeremy M. Shefner, Antonio Musaro, Shyuan T. Ngo, Christian Lunetta, Frederik J. Steyn, Richard Robitaille, Mamede De Carvalho, Seward Rutkove, Albert C. Ludolph, Luc Dupuis
Summary: Amyotrophic lateral sclerosis (ALS), a major motor neuron disease, has long been considered as primarily affecting motor neurons and neuromuscular junctions, with muscle changes being secondary. However, recent studies have shown that skeletal muscle dysfunction might contribute to muscle weakness, as well as the degeneration of neuromuscular junctions and motor neurons in ALS. This article explores the various potential roles of skeletal muscle in ALS pathophysiology and compares ALS to other motor neuron diseases, providing insights for future research and treatment.
Article
Physiology
Matthew J. Fogarty, Sabhya Rana, Carlos B. Mantilla, Gary C. Sieck
Summary: Type S and FR motor units, consisting of smaller phrenic motor neurons, are regularly recruited to meet indefatigable ventilatory requirements. In contrast, Type FF motor units, consisting of larger phrenic motor neurons, are infrequently recruited for expulsive straining and airway defense maneuvers. This difference in activation history is reflected in the mitochondrial volume density (MVD), with smaller PhMNs having higher MVD than larger PhMNs. In proximal dendrites, this trend is reversed, with larger PhMNs having higher MVD than smaller PhMNs, likely due to the maintenance requirements for the larger dendritic arbor of FF PhMNs.
JOURNAL OF APPLIED PHYSIOLOGY
(2023)
Article
Neurosciences
Matthew J. J. Fogarty, Wen-Zhi Zhan, Vincent F. F. Simmon, Peter W. W. Vanderklish, Stella T. T. Sarraf, Gary C. C. Sieck
Summary: This study investigates the effects of C2SH on diaphragm muscle and transdiaphragmatic pressure, as well as the potential therapeutic effect of SPG302. The results show that immediate deficits in diaphragm EMG activity and transdiaphragmatic pressure occur after C2SH surgery, while treatment with SPG302 can enhance the recovery of diaphragm EMG and transdiaphragmatic pressure within 14 days post-surgery.
JOURNAL OF PHYSIOLOGY-LONDON
(2023)
Article
Neurosciences
Matthew J. Fogarty, Debanjali Dasgupta, Obaid U. Khurram, Gary C. Sieck
Summary: Inhibition of TrkB signaling alone in adult TrkBF616 rats leads to loss of phrenic motor neurons, morphological degeneration, and deficits in retrograde axonal uptake/transport.
MOLECULAR AND CELLULAR NEUROSCIENCE
(2023)
Article
Multidisciplinary Sciences
Ramon Martinez-Mamol, Rosina Giordano-Santini, Eva Kaulich, Ann-Na Cho, Magdalena Przybyla, Md Asrafuzzaman Riyadh, Emilija Robinson, Keng Yih Chew, Rumelo Amor, Frederic A. Meunier, Giuseppe Balistreri, Kirsty R. Short, Yazi D. Ke, Lars M. Ittner, Massimo A. Hilliard
Summary: Viruses, including SARS-CoV-2, can infect the brain and cause severe neurological symptoms through the fusion of neurons and glia. This fusion is mediated by the viral fusogen and leads to the formation of multicellular syncytia, as well as the spread of molecules and organelles. Furthermore, the fusion severely compromises neuronal activity. These findings contribute to our understanding of the mechanisms by which viruses affect the nervous system and cause neuropathology.
Review
Clinical Neurology
Albert Ludolph, Luc Dupuis, Edward Kasarskis, Frederik Steyn, Shyuan Ngo, Christopher McDermott
Summary: Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease with non-motor symptoms. Nutritional status and metabolic balance have been found to contribute to faster disease progression and earlier death. Cellular changes, including mitochondrial dysfunction, are also shown to contribute to bioenergetic failure in ALS. Modifying energy balance in ALS shows potential as a treatment option and multiple clinical trials are underway.
NATURE REVIEWS NEUROLOGY
(2023)
Article
Cell & Tissue Engineering
Timothy J. Tracey, Leanne Jiang, Melinder K. Gill, Samara N. Ranie, Dmitry A. Ovchinnikov, Ernst J. Wolvetang, Shyuan T. Ngo
Summary: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease, and the TDP-43 protein plays a crucial role in its pathophysiology. This study used the CRISPR-Cas9 system to introduce a heterozygous missense mutation (c.1144G > A, p.A382T) in exon 6 of the TARDBP gene into iPSCs derived from a healthy individual. The edited iPSCs maintained normal cellular morphology, pluripotency markers expression, tri-lineage differentiation ability, and karyotype.
STEM CELL RESEARCH
(2023)
Article
Multidisciplinary Sciences
Tarika Vijayaraghavan, Samiksha Dhananjay, Xue Yan Ho, Rosina Giordano-Santini, Massimo Hilliard, Brent Neumann
Summary: Axonal fusion is a neuronal repair mechanism that reconnects severed axon fragments. The dynamin protein DYN-1 in Caenorhabditis elegans is identified as a key component in axonal fusion, regulating the levels of the fusogen protein EFF-1 post-injury.
Article
Biochemical Research Methods
Bahaa Al-mhanawi, Marta Boira Marti, Sean D. Morrison, Pallavi Gupta, Maath Alani, Peter G. Noakes, Ernst J. Wolvetang, Mohammed R. Shaker
Summary: This article presents a method to generate oligodendrocyte-enriched brain organoids for studying human white matter diseases. The method involves neuroectoderm differentiation, development of neural spheroids, transferal to Matrigel, and the development and application of the brain organoids.
Meeting Abstract
Biochemistry & Molecular Biology
Sean Morrison, Mohammed Shaker, Giovanni Pietrogrande, Ernst Wolvetang, Peter Noakes
JOURNAL OF NEUROCHEMISTRY
(2023)