Correction
Biochemistry & Molecular Biology
Marcus S. Dyer, Laura A. Reale, Katherine E. Lewis, Adam K. Walker, Tracey C. Dickson, Adele Woodhouse, Catherine A. Blizzard
Summary: Amyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative disease characterized by mislocalisation of TDP-43 protein from the nucleus to the cytoplasm. Experimental findings suggest that mislocalised TDP-43 can lead to altered function of motor cortex neurons, potentially causing hyperexcitability and synaptic dysfunction.
JOURNAL OF NEUROCHEMISTRY
(2021)
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
Immunology
Yuan Chao Xue, Huitao Liu, Yasir Mohamud, Amirhossein Bahreyni, Jingchun Zhang, Neil R. Cashman, Honglin Luo
Summary: This study identifies CVB3 infection as a risk factor for early onset and accelerated progression of ALS, provides evidence for the potential association between the virus and ALS, and discovers that early administration of ribavirin can rescue ALS-like pathology and symptoms induced by CVB3 infection.
JOURNAL OF NEUROINFLAMMATION
(2022)
Review
Biochemistry & Molecular Biology
Kazuhide Asakawa, Hiroshi Handa, Koichi Kawakami
Summary: TDP-43 is an evolutionarily conserved hnRNP encoded by the TARDBP gene, which plays a crucial role in regulating RNA metabolism in ALS. Studies using cellular and animal models have provided insights into potential links between TDP-43 and the vulnerability of motor neurons in ALS.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2021)
Article
Neurosciences
Ryan A. Milstead, Christopher D. Link, Zuoshang Xu, Charles A. Hoeffer
Summary: This study suggests that loss of TDP-43 function could contribute to neuropathology by increasing dsRNA deposition and subsequent innate immune system activation, leading to the development of severe neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS).
Article
Clinical Neurology
Shintaro Tsuboguchi, Yuka Nakamura, Tomohiko Ishihara, Taisuke Kato, Tokiharu Sato, Akihide Koyama, Hideki Mori, Yuka Koike, Osamu Onodera, Masaki Ueno
Summary: This study demonstrates that mutant TDP-43 can spread across neural connections and induce degenerative processes in the motor circuits, leading to motor neuron degeneration and muscle atrophy.
ACTA NEUROPATHOLOGICA
(2023)
Article
Cell Biology
Kelsey L. Krus, Amy Strickland, Yurie Yamada, Laura Devault, Robert E. Schmidt, A. Joseph Bloom, Jeffrey Milbrandt, Aaron DiAntonio
Summary: The reduction of STMN2 protein due to TDP-43 pathology is likely to be a contributing factor to the development of ALS. Knocking out the STMN2 gene in mice results in neuropathy and NMJ denervation, which is similar to the pathological changes observed in ALS.
Article
Neurosciences
Tariq Afroz, Elodie Chevalier, Mickael Audrain, Christopher Dumayne, Tamar Ziehm, Roger Moser, Anne-Laure Egesipe, Lorene Mottier, Monisha Ratnam, Manuela Neumann, Daniel Havas, Romain Ollier, Kasia Piorkowska, Mayank Chauhan, Alberto B. Silva, Samjhana Thapa, Jan Stohr, Andrej Bavdek, Valerie Eligert, Oskar Adolfsson, Peter T. Nelson, Silvia Porta, Virginia M. -Y. Lee, Andrea Pfeifer, Marie Kosco-Vilbois, Tamara Seredenina
Summary: Effective therapies urgently needed to target TDP-43 pathology, which is closely associated with devastating diseases such as FTLD-TDP and ALS. Our approach is to develop a TDP-43-specific immunotherapy that limits neuronal damage while maintaining physiological TDP-43 function. Targeting the C-terminal domain of TDP-43 reduces pathology and neurotoxicity through microglia engagement.
NEUROBIOLOGY OF DISEASE
(2023)
Article
Genetics & Heredity
Tanzeen Yusuff, Ya-Chu Chang, Tzu-Kang Sang, George R. Jackson, Shreyasi Chatterjee
Summary: The codon optimized TDP-43 model demonstrates the formation of toxic protein aggregates through a gain-of-function mechanism and the activation of cellular autophagy pathways, providing insights into the disease mechanism of TDP-43 proteinopathies.
FRONTIERS IN GENETICS
(2023)
Article
Biochemistry & Molecular Biology
Niharika Nag, Timir Tripathi
Summary: Nucleocytoplasmic transport is impaired in C9-ALS/FTLD, and a protein called FG-Nup62 is found to be mislocalized and colocalized with TDP-43, promoting its transition from liquid to solid state. This study highlights the involvement of Nup62 in the pathogenesis of ALS/FTLD and its interaction with TDP-43.
ACS CHEMICAL NEUROSCIENCE
(2022)
Article
Cell Biology
Miguel A. Rubio, Mireia Herrando-Grabulosa, Roser Velasco, Israel Blasco, Monica Povedano, Xavier Navarro
Summary: This study found increased levels of TDP-43 in the skin of ALS patients, which may serve as a potential biomarker for early diagnosis of ALS.
Article
Clinical Neurology
Fei Mao, John L. Robinson, Travis Unger, Marijan Posavi, Defne A. Amado, Lauren Elman, Murray Grossman, David A. Wolk, Edward B. Lee, Vivianna M. Van Deerlin, Silvia Porta, Virginia M. Y. Lee, John Q. Trojanowski, Alice S. Chen-Plotkin
Summary: The study revealed that genotypes at the TMEM106B locus and hexanucleotide repeat expansions in C9orf72 were associated with the severity and regional distribution of TDP-43 pathology in neurodegenerative diseases. While C9orf72 expansions were linked to greater TDP-43 pathology in ALS, the relationship between TMEM106B genotype and TDP-43 pathology remained consistent. Manipulating TMEM106B levels showed a causal role in modifying the development of TDP-43 proteinopathy.
ACTA NEUROPATHOLOGICA
(2021)
Review
Biochemistry & Molecular Biology
Yoshitaka Tamaki, Makoto Urushitani
Summary: This review provides an overview of the current understanding of TDP-43 biology and pathology, highlighting the cellular processes involved in the pathogenesis of ALS and FTLD, including post-translational modifications, RNA metabolism, liquid-liquid phase separation, proteolysis, and the potential prion-like propagation of TDP-43 inclusions.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Oliver J. Ziff, Benjamin E. Clarke, Doaa M. Taha, Hamish Crerar, Nicholas M. Luscombe, Rickie Patani
Summary: This study reveals that astrocytes in amyotrophic lateral sclerosis (ALS) exhibit inflammatory reactive features and suppress neuronal support mechanisms. These findings offer potential therapeutic targets for ALS.
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)
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
Stavroula Tsitkanou, Paul A. Della Gatta, Gavin Abbott, Marita A. Wallace, Angus Lindsay, Frederico Gerlinger-Romero, Adam K. Walker, Victoria C. Foletta, Aaron P. Russell
Summary: Skeletal muscle dysfunction may contribute to the progression and severity of ALS. In an ALS mouse model, suppression of miR-23a accelerates disease progression.
NEUROBIOLOGY OF DISEASE
(2022)
Review
Neurosciences
Sean S. Keating, Rebecca San Gil, Molly E. Swanson, Emma L. Scotter, Adam K. Walker
Summary: Our understanding of amyotrophic lateral sclerosis and frontotemporal dementia has greatly improved since the discovery of TAR DNA-binding protein 43 (TDP-43) inclusions as the key pathology. Recent studies have provided insights into the function of TDP-43 and its dysfunction in these neurodegenerative diseases. The formation and aggregation of pathological TDP-43 species contribute to cellular dysfunction and toxicity, and various protein homeostasis mechanisms play a role in combating TDP-43 aggregation and promoting disease progression. Future therapeutic strategies targeting TDP-43 clearance show promise in treating these diseases.
PROGRESS IN NEUROBIOLOGY
(2022)
Article
Neurosciences
Akram Zamani, Adam K. Walker, Ben Rollo, Katie L. Ayers, Raysha Farah, Terence J. O'Brien, David K. Wright
Summary: This study found that the glymphatic system is impaired in the early stages of amyotrophic lateral sclerosis (ALS), leading to progressive neurodegeneration and disrupted glymphatic function. This suggests that the glymphatic system could be a potential therapeutic target for ALS treatment.
TRANSLATIONAL NEURODEGENERATION
(2022)
Editorial Material
Genetics & Heredity
Adekunle T. Bademosi, Adam K. Walker
Summary: Loss of TDP-43 function can lead to the development of neurodegenerative diseases such as ALS and FTD. Recent studies have also found that this loss of function results in the inclusion of cryptic exons in certain mRNAs, shedding light on new disease mechanisms.
TRENDS IN GENETICS
(2022)
Article
Biochemistry & Molecular Biology
Sean S. Keating, Adekunle T. Bademosi, Rebecca San Gil, Adam K. Walker
Summary: Aggregation of TDP-43 is the hallmark of neurodegenerative diseases, involving depletion, mislocalisation, and post-translational modification of normal nuclear TDP-43. Oxidative stress triggers liquid-liquid phase separation of TDP-43, while RNA-binding deficiency and acetylation mimicry lead to sequestration of normal nuclear TDP-43 into dynamic anisosomes. Nuclear or cytoplasmic aggregation-prone TDP-43 mutants form phosphorylated inclusions that immobilize and insolubilize endogenous TDP-43, indicating pathological transition. Overall, these findings highlight the importance of RNA-binding deficiency and post-translational modifications in driving TDP-43 aggregation and dysfunction in neurodegenerative diseases.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Wei Luan, Amanda L. L. Wright, Heledd Brown-Wright, Sheng Le, Rebecca San Gil, Lidia Madrid San Martin, Karen Ling, Paymaan Jafar-Nejad, Frank Rigo, Adam K. K. Walker
Summary: TDP-43 pathology is a major characteristic of ALS and FTD. Activation of cell stress pathways may contribute to the dysfunction of TDP-43. In a transgenic mouse model, several integrated stress response effectors were upregulated before disease onset, followed by pro-apoptotic signaling after the onset of motor phenotypes. Suppression of Chop had no effect on TDP-43 pathology or disease phenotypes. Precise temporal modulation of cell stress and death pathways may protect against neurodegeneration in ALS and FTD.
MOLECULAR PSYCHIATRY
(2023)
Article
Clinical Neurology
Rosemary M. Clark, Courtney M. Clark, Katherine E. A. Lewis, Marcus S. Dyer, Jyoti A. Chuckowree, Joshua A. Hoyle, Catherine A. Blizzard, Tracey C. Dickson
Summary: Objective: The objective of this study was to investigate the therapeutic potential and role of neuropeptide Y (NPY) in amyotrophic lateral sclerosis (ALS). Methods: NPY expression in post-mortem motor cortex tissue of ALS patients and controls was quantified, and the effect of NPY on ALS cortical pathophysiology was examined using in vitro experiments. The impact of NPY on ALS disease trajectory was assessed through intranasal delivery of NPY and selective NPY receptor agonists and antagonists in ALS mouse models. Results: Increased NPY expression was observed in the motor cortex of ALS patients, and NPY was found to ameliorate ALS hyperexcitability in vitro. Intranasal delivery of NPY and NPY receptor modulation improved survival and motor deficits in ALS mice. Interpretation: These findings demonstrate the potential of non-invasive brain-targeted interventions in ALS and suggest NPY Y1R antagonism as a novel strategy to improve ALS motor function.
ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY
(2023)
Article
Neuroimaging
Akram Zamani, Adam K. Walker, Ben Rollo, Katie L. Ayers, Raysha Farah, Terence J. O. Brien, David K. Wright
Summary: This study investigates the potential of neurite orientation dispersion and density imaging and diffusion tensor imaging (DTI) in detecting microstructural changes in an experimental model of ALS. The results suggest that these advanced neuroimaging techniques can detect significant changes in the early stages of the disease, providing valuable insights into the pathophysiological progression of ALS and potentially aiding in early diagnosis.
NEUROIMAGE-CLINICAL
(2022)
Article
Biochemistry & Molecular Biology
Pei-Yang Gao, Ya-Nan Ou, Yi-Ming Huang, Zhi-Bo Wang, Yan Fu, Ya-Hui Ma, Qiong-Yao Li, Li-Yun Ma, Rui-Ping Cui, Yin-Chu Mi, Lan Tan, Jin-Tai Yu
Summary: Liver function may play a role in the progression of Alzheimer's disease. The study found that as AD progressed, certain liver function markers increased while others decreased. The relationship between liver function and CSF AD biomarkers indicates a potential mediation effect on cognition.
JOURNAL OF NEUROCHEMISTRY
(2024)