Article
Virology
Lili Zhang, Jiaxin Yang, Huili Li, Zhe Zhang, Zhilin Ji, Lirong Zhao, Wei Wei
Summary: This study found that EV-D68 infection leads to cleavage and subcellular translocation of TDP-43 protein, promoting its pathogenic aggregation and cellular toxicity. It also identified a potential inhibitor, lopinavir, for the EV-D68 3C protease. This study provides the first evidence of TDP-43 dysregulation in EV-D68 pathogenesis.
JOURNAL OF VIROLOGY
(2023)
Article
Cell Biology
Qiang Zhang, Seigo Terawaki, Daisuke Oikawa, Yoshinori Okina, Yoshinosuke Usuki, Hidefumi Ito, Fuminori Tokunaga
Summary: TAR DNA-binding protein 43 (TDP-43) is a component of inclusions in the brains and spines of ALS patients, and its aggregation is influenced by linear ubiquitination. Inhibition of linear ubiquitination can ameliorate TDP-43 proteinopathy.
Article
Multidisciplinary Sciences
Lisa J. Oyston, Stephanie Ubiparipovic, Lauren Fitzpatrick, Marianne Hallupp, Lauren M. Boccanfuso, John B. Kwok, Carol Dobson-Stone
Summary: This study developed a novel quantitative method to detect the distribution of TDP-43 and FUS within cells, which can be used to identify FTD/ALS-causative mutations. Additionally, it was found that pharmacological interventions and mutations in secondary genes can also affect the distribution of these proteins within cells.
SCIENTIFIC REPORTS
(2021)
Article
Chemistry, Multidisciplinary
Lixin Yang, Yllza Jasiqi, Agnes Zettor, Oscar Vadas, Jeanne Chiaravalli, Fabrice Agou, Hilal A. Lashuel
Summary: The native state stabilization of TDP-43 is a viable strategy for treating TDP-43 proteinopathies. By designing C-terminal substitutions and binding native oligonucleotide ligands, the monomeric state of TDP-43 can be stabilized and prevent aggregation and phase separation.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Biochemistry & Molecular Biology
Manuela Perez-Berlanga, Vera Wiersma, Aurelie Zbinden, Laura De Vos, Ulrich Wagner, Chiara Foglieni, Izaskun Mallona, Katharina M. Betz, Antoine Clery, Julien Weber, Zhongning Guo, Ruben Rigort, Pierre de Rossi, Ruchi Manglunia, Elena Tantardini, Sonu Sahadevan, Oliver Stach, Marian Hruska-Plochan, Frederic H-T Allain, Paolo Paganetti, Magdalini Polymenidou
Summary: Aggregation of the RNA-binding protein TDP-43 is the key neuropathological feature of neurodegenerative diseases. Our study reveals that oligomerization and RNA binding play important roles in TDP-43 stability, function, and subcellular localization. We also found that the location of TDP-43 aggregates is determined by different pathways, shedding light on the origins of pathological species observed in TDP-43 proteinopathy patients.
Article
Biology
Ursa Susnjar, Neva Skrabar, Anna-Leigh Brown, Yasmine Abbassi, Hemali Phatnani, Andrea Cortese, Cristina Cereda, Enrico Bugiardini, Rosanna Cardani, Giovanni Meola, Michela Ripolone, Maurizio Moggio, Maurizio Romano, Maria Secrier, Pietro Fratta, Emanuele Buratti
Summary: This study investigates the role of TDP-43 in muscle and neuronal cells, and discovers the association between aberrant splicing of TDP-43 and disease development. Using RNA-seq technology, the authors compare the differences in TDP-43-mediated RNA processing between muscle and neuronal cells. The results demonstrate the cell-type characteristic behavior of TDP-43, which is influenced by the expression of RNA-binding proteins and defines cell-type specific splicing. Some splicing events identified in both cell lines are also TDP-43-dependent in human cells, and the inclusion levels of alternative exons are altered in patients with FTLD and IBM.
COMMUNICATIONS BIOLOGY
(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
Biochemistry & Molecular Biology
Marcus S. Dyer, Laura A. Reale, Katherine E. Lewis, Adam K. Walker, Tracey C. Dickson, Adele Woodhouse, Catherine A. Blizzard
Summary: ALS is a chronic neurodegenerative disease characterized by mislocalisation of the TDP-43 protein from the nucleus to the cytoplasm. Research in mouse models indicates that mislocalised TDP-43 causes intrinsic hyperexcitability and synaptic dysfunction in motor cortex neurons.
JOURNAL OF NEUROCHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Lilian Tsai-Wei Lin, Abdul Razzaq, Sonja E. Di Gregorio, Soojie Hong, Brendan Charles, Marilene H. Lopes, Flavio Beraldo, Vania F. Prado, Marco A. M. Prado, Martin L. Duennwald
Summary: Protein misfolding is a key characteristic of most neurodegenerative diseases. Molecular chaperones such as Hsp90 and its co-chaperone Sti1 play a role in modulating the toxicity associated with TDP-43 misfolding and inclusion formation. Impaired Hsp90 function sensitizes cells to TDP-43 toxicity, while Sti1 specifically interacts with TDP-43 and strongly modulates its toxicity in a dose-dependent manner.
Article
Pharmacology & Pharmacy
Shinrye Lee, Myungjin Jo, Hye Eun Lee, Yu-Mi Jeon, Seyeon Kim, Younghwi Kwon, Junghwa Woo, Shin Han, Ji Young Mun, Hyung-Jun Kim
Summary: HEXA-018 activates autophagy through the AMPK-ULK1 pathway in an mTOR-independent manner, reducing neurotoxicity and mitochondrial dysfunction induced by oxidative stress, and showing significant efficacy in TDP-43 proteinopathy models.
FRONTIERS IN PHARMACOLOGY
(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
Biochemistry & Molecular Biology
Guiomar Rodriguez-Perinan, Ana de la Encarnacion, Fermin Moreno, Adolfo Lopez de Munain, Ana Martinez, Angeles Martin-Requero, Carolina Alquezar, Fernando Bartolome
Summary: LOF mutations in GRN gene cause FTLD-TDP, and mitochondrial dysfunction is involved in the pathogenesis of PGRN deficiency-associated FTLD-TDP. PGRN deficiency induces mitochondrial depolarization, elevated ROS production, and reduced ATP levels. The accumulation of damaged mitochondria and autophagy dysfunction were observed in PGRN-deficient cells, which can be rescued by CK-1 delta inhibitors.
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
Han-Cheon Kim, Yan Zhang, Peter H. H. King, Liang Lu
Summary: ALS is a fatal neurodegenerative disease characterized by motor neuron damage and TDP-43 proteinopathy. This study shows that miR-183-5p is aberrantly upregulated in ALS patients and regulates TDP-43 protein levels through the SQSTM1/p62 pathway. It provides a novel mechanism linking abnormal RNA processing and protein degradation in ALS pathogenesis.
JOURNAL OF NEUROCHEMISTRY
(2023)
Article
Environmental Sciences
Guoliang Li, Kaidong Wang, Kai Zuo, Ge Shi, Qian Cai, Min Huang
Summary: In this paper, researchers investigated the effects of Atrazine (ATR) exposure on dopaminergic neurons. They found that ATR exposure can cause aggregation and position change of transactive response DNA-binding protein-43 (TDP-43), which may indicate mitochondrial dysfunction and damage to dopaminergic neurons. The study suggests that TDP-43 could serve as a potential effector marker of dopaminergic neuron damage caused by ATR exposure.
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
(2023)
Article
Medicine, General & Internal
Frances Theunissen, Loren L. Flynn, Ryan S. Anderton, P. Anthony Akkari
Summary: This article discusses the role of recent discoveries of short structural variations (SSVs) in ALS and how these findings can be applied to future clinical trials. These discoveries help reduce participant heterogeneity and improve outcomes of ALS clinical trials.
Article
Neurosciences
Stephanie L. Rayner, Shu Yang, Natalie E. Farrawell, Cyril J. Jagaraj, Flora Cheng, Jennilee M. Davidson, Luan Luu, Alberto G. Redondo, Alberto Rabano, Daniel Borrego-Hernandez, Julie D. Atkin, Marco Morsch, Ian P. Blair, Justin J. Yerbury, Roger Chung, Albert Lee
Summary: This study reveals a direct ubiquitylation mechanism for TDP-43 mediated by cyclin F, providing important insights into the regulation of cyclin F-mediated TDP-43 turnover and clues towards understanding the molecular origins of the ubiquitylated TDP-43 inclusions that are the hallmark feature in ALS and FTD.
NEUROBIOLOGY OF DISEASE
(2022)
Article
Genetics & Heredity
Loren L. Flynn, Ruohan Li, Ianthe L. Pitout, May T. Aung-Htut, Leon M. Larcher, Jack A. L. Cooper, Kane L. Greer, Alysia Hubbard, Lisa Griffiths, Charles S. Bond, Steve D. Wilton, Archa H. Fox, Sue Fletcher
Summary: Modified oligonucleotides and nucleic acid analogues have potential therapeutic applications in human disease. However, the modifications may have unexpected effects on physicochemical and biological properties. This study reveals the chemistry-specific effects of modified or unmodified oligonucleotides with phosphorothioate linkages on subnuclear organelles, nuclear protein distribution, nuclear inclusions, and RNA processing in primary human fibroblasts and other cultured cells.
FRONTIERS IN GENETICS
(2022)
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)
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)
Editorial Material
Biochemical Research Methods
Hannah Jane Suddull, Livia Rosa-Fernandes, Albert Lee
EXPERT REVIEW OF PROTEOMICS
(2023)
Article
Clinical Neurology
Natalie Grima, Sidong Liu, Dean Southwood, Lyndal Henden, Andrew Smith, Albert Lee, Dominic B. Rowe, Susan D'Silva, Ian P. Blair, Kelly L. Williams
Summary: Peripheral blood RNA-seq can identify diagnostic biomarkers in ALS patients and distinguish molecular subtypes, but its prognostic value needs further investigation.
NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY
(2023)
Meeting Abstract
Rheumatology
Julia Pytte, Maria Van Loenhout, Frank Mastaglia, Ian James, Loren L. Flynn, Gabriella MacDougall, Kelly Beer, Jerome Coudert, Anu Sooda, P. Anthony Akkari, Merilee Needham
CLINICAL AND EXPERIMENTAL RHEUMATOLOGY
(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)