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)
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
Multidisciplinary Sciences
Elaine Pirie, Chang-Ki Oh, Xu Zhang, Xuemei Han, Piotr Cieplak, Henry R. Scott, Amanda K. Deal, Swagata Ghatak, Fernando J. Martinez, Gene W. Yeo, John R. Yates, Tomohiro Nakamura, Stuart A. Lipton
Summary: This study reveals that environmentally induced nitrosative stress can trigger protein aggregation and cell-to-cell spread, leading to abnormal aggregation of TDP-43 in ALS/FTD. These processes also interfere with neuronal function, contributing to the progression of the diseases.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Biochemistry & Molecular Biology
S. Preethi, Vidhya Bharathi, Basant K. Patel
Summary: TDP-43 proteinopathy is associated with neurodegenerative diseases such as ALS and FTLD-TDP, with implications of metal ion dyshomeostasis. Zn2+ was found to enhance in vitro amyloid-like aggregation of TDP-43, potentially through multiple binding sites.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2021)
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
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
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)
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
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
Neurosciences
Marc Shenouda, Shangxi Xiao, Laura MacNair, Agnes Lau, Janice Robertson
Summary: Neuronal cytoplasmic aggregation and ubiquitination of TDP-43 is a common pathology in ALS and FTLD. Various truncated variants of TDP-43, generated through proteolytic cleavage and abnormal RNA processing, contribute to the pathophysiology. This study identifies a new C-terminally truncated variant and explores its functional relevance.
FRONTIERS IN NEUROSCIENCE
(2022)
Review
Neurosciences
Ruxandra Dafinca, Paola Barbagallo, Kevin Talbot
Summary: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by mislocalization and aggregation of specific proteins in the cytoplasm. Research indicates that endoplasmic reticulum stress and mitochondrial dysfunction play a central role in the pathogenesis of ALS, potentially serving as important therapeutic targets.
FRONTIERS IN CELLULAR NEUROSCIENCE
(2021)
Review
Clinical Neurology
Lindsey R. Hayes, Petr Kalab
Summary: Nuclear clearance and cytoplasmic mislocalization of TDP-43 protein are pathological features of neurodegenerative disorders. The mislocalization of TDP-43 leads to neurodegeneration through disruption of RNA processing and cellular functions. Therapies for TDP-43 primarily focus on clearing TDP-43 aggregates, and future strategies aim to address the upstream causes of TDP-43 disruption.
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)
Review
Biochemistry & Molecular Biology
Alistair Wood, Yuval Gurfinkel, Nicole Polain, Wesley Lamont, Sarah Lyn Rea
Summary: ALS and FTLD are neurodegenerative disorders with pathological, clinical, and genetic overlaps. The primary pathological protein, TDP-43, is observed in aggregates in affected tissues in majority of cases. Disease pathogenesis involves changes in RNA splicing, abnormal stress granules, mitochondrial dysfunction, and other cellular processes.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
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
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)