Editorial Material
Cell Biology
Abubakar Wani, Conrad C. Weihl
Summary: VCP, a member of the AAA+ protein family, plays a critical role in neuronal survival in fronto-temporal dementia with TARDBP inclusions. Mutations in VCP lead to neurodegeneration through various mechanisms, making it a potential therapeutic target for restoring protein homeostasis in FTLD-TARDBP 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)
Editorial Material
Cell Biology
Yuan-Ping Chu, Pei-Chuan Ho, Kuen-Jer Tsai
Summary: TTR plays a neuroprotective role in preventing amyloid-beta deposition in Alzheimer's disease (AD). Dysregulation of TARDBP expression leads to cytoplasmic aggregation associated with neurological disorders such as FTLD-TDP and ALS. It was found that excessive TARDBP upregulates TTR, and both proteins co-accumulate in FTLD-TDP. TTR promotes autophagy activity and facilitates TARDBP degradation, functioning in bi-directional regulation.
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.
Review
Biochemistry & Molecular Biology
Yuichi Riku, Danielle Seilhean, Charles Duyckaerts, Susana Boluda, Yohei Iguchi, Shinsuke Ishigaki, Yasushi Iwasaki, Mari Yoshida, Gen Sobue, Masahisa Katsuno
Summary: TDP-43 is a pathologic protein implicated in ALS and FTLD, with mislocalization and aggregation potentially contributing to neurotoxicity. Research focuses on examining TDP-43 pathology in autopsied patients and understanding pathways related to neuronal dysfunction in TDP-43-related diseases.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
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
Multidisciplinary Sciences
Yanjun Zhou, Nanqu Huang, Yuanyuan Li, Zhisheng Ba, Yong Luo
Summary: This study investigated the protective effect of icaritin (ICT) in SH-SY5Y cells infected with TAR DNA-binding domain protein 43 (TDP-43) and its underlying mechanism by examining the expression of autophagy-related proteins. The results showed that ICT intervention increased cell viability, decreased TDP-43 expression, and reduced the expression of cleaved Caspase-3, Beclin-1, and LC3-II/I, while increasing the expression of p62. This suggests that ICT has a protective effect on TDP-43-induced neuronal cell injury by reducing TDP-43 protein expression and inhibiting autophagy.
Review
Geriatrics & Gerontology
Benjamin I. Nilaver, Henryk F. Urbanski
Summary: TDP-43 plays a crucial role in cell functions, but dysfunction is associated with various brain diseases. Recent research suggests that dysfunction of TDP-43 may precede the development of these diseases and explains why it is implicated in a wide range of neurodegenerative disorders. Dysregulation of TDP-43 can impact gene expression, mRNA stability, and the function and coordination of pathways regulated by TDP-43.
FRONTIERS IN AGING NEUROSCIENCE
(2023)
Article
Neurosciences
Nirma D. Perera, Doris Tomas, Nayomi Wanniarachchillage, Brittany Cuic, Sophia J. Luikinga, Valeria Rytova, Bradley J. Turner
Summary: Autophagy plays a crucial role in maintaining cell homeostasis, but excessive induction may accelerate neurodegenerative diseases. This study demonstrated that stimulating autophagy with rilmenidine exacerbated the ALS phenotype in a TDP-43 mouse model, likely through excessive mitochondrial clearance in motor neurons. Balancing autophagy stimulation and hyperactive mitophagy is essential in ALS and other neurodegenerative diseases.
NEUROBIOLOGY OF DISEASE
(2021)
Article
Biochemistry & Molecular Biology
Nikolina Prtenjaca, Matea Rob, Muhammad S. Alam, Andrea Markovinovic, Cristiana Stuani, Emanuele Buratti, Ivana Munitic
Summary: Deficiency of optineurin protein leads to upregulation of TDP-43 protein expression in microglial cells, and this upregulation is not affected by inflammatory stimuli. This finding is important for understanding the pathogenesis of ALS.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Virology
Sei-Kyoung Park, Sangeun Park, Susan W. Liebman
Summary: When human TDP-43 is overexpressed in yeast, it forms toxic cytoplasmic aggregates and inhibits autophagy. Deletion of genes PBP1 and tip41 Delta reduces TDP-43 toxicity and restores autophagy.
Article
Geriatrics & Gerontology
Judith Canto-Santos, Laura Valls-Roca, Ester Tobias, Francesc Josep Garcia-Garcia, Mariona Guitart-Mampel, Anna Esteve-Codina, Beatriz Martin-Mur, Mercedes Casado, Rafael Artuch, Estel Solsona-Vilarrasa, Jose Carlos Fernandez-Checa, Carmen Garcia-Ruiz, Carles Rentero, Carlos Enrich, Pedro J. J. Moreno-Lozano, Jose Cesar Milisenda, Francesc Cardellach, Josep M. M. Grau-Junyent, Gloria Garrabou
Summary: In this study, molecular disturbances were found in fibroblast samples from IBM patients, including abnormal gene expression related to inflammation, mitochondria, and cell cycle regulation, as well as functional changes in inflammatory, autophagy, mitochondrial, and metabolic processes. These findings contribute to a better understanding of the pathogenesis of IBM and provide insights for the identification of new biomarkers and therapeutic strategies.
JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE
(2023)
Article
Clinical Neurology
Sai Sampath Thammisetty, Laurence Renaud, Vincent Picher-Martel, Yuan Cheng Weng, Frederic Calon, Stephan Saikali, Jean-Pierre Julien, Jasna Kriz
Summary: Vascular dementia is a common form of dementia in the aging population, with molecular mechanisms involving TDP-43 mislocalization and cognitive impairments. A new study found that a specific drug can mitigate TDP-43 pathology, enhance autophagy, and ameliorate cognitive and motor deficits in mice with chronic brain hypoperfusion.
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.
Article
Multidisciplinary Sciences
Giovanni De Marco, Annarosa Lomartire, Umberto Manera, Antonio Canosa, Maurizio Grassano, Federico Casale, Giuseppe Fuda, Paolina Salamone, Maria Teresa Rinaudo, Sebastiano Colombatto, Cristina Moglia, Adriano Chio, Andrea Calvo
Summary: This study investigates the relationship between proteins associated with ALS and intracellular calcium accumulation. The findings suggest that intracellular calcium accumulation leads to decreased levels of several proteins and is associated with the activation of protein degradation and autophagy. These findings contribute to understanding the mechanisms of ALS and identifying new therapeutic targets.
SCIENTIFIC REPORTS
(2022)
Article
Rheumatology
Thomas E. Lloyd, Lisa Christopher-Stine, Iago Pinal-Fernandez, Eleni Tiniakou, Michelle Petri, Alan Baer, Sonye K. Danoff, Katherine Pak, Livia A. Casciola-Rosen, Andrew L. Mammen
ARTHRITIS CARE & RESEARCH
(2016)
Article
Rheumatology
Iago Pinal-Fernandez, Maria Casal-Dominguez, John A. Carrino, Arash H. Lahouti, Pari Basharat, Jemima Albayda, Julie J. Paik, Shivani Ahlawat, Sonye K. Danoff, Thomas E. Lloyd, Andrew L. Mammen, Lisa Christopher-Stine
ANNALS OF THE RHEUMATIC DISEASES
(2017)
Article
Radiology, Nuclear Medicine & Medical Imaging
Avneesh Chhabra, John A. Carrino, Sahar J. Farahani, Gaurav K. Thawait, Charlotte J. Sumner, Vibhor Wadhwa, Vinay Chaudhary, Thomas E. Lloyd
JOURNAL OF MAGNETIC RESONANCE IMAGING
(2016)
Letter
Cardiac & Cardiovascular Systems
Pari Basharat, Arash H. Lahouti, Julie J. Paik, Jemima Albayda, Iago Pinal-Fernandez, Tanmayee Bichile, Thomas E. Lloyd, Sonye K. Danoff, Livia Casciola-Rosen, Andrew L. Mammen, Lisa Christopher-Stine
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
(2016)
Article
Neurosciences
Yun Ha Jeong, Jonathan P. Ling, Sophie Z. Lin, Aneesh N. Donde, Kerstin E. Braunstein, Elisa Majounie, Bryan J. Traynor, Katherine D. LaClair, Thomas E. Lloyd, Philip C. Wong
MOLECULAR NEURODEGENERATION
(2017)
Article
Clinical Neurology
Thomas E. Lloyd, Iago Pinal-Fernandez, E. Harlan Michelle, Lisa Christopher-Stine, Katherine Pak, Ned Sacktor, Andrew L. Mammen
Article
Neurosciences
Jonathan C. Grima, J. Gavin Daigle, Nicolas Arbez, Kathleen C. Cunningham, Ke Zhang, Joseph Ochaba, Charlene Geater, Eva Morozko, Jennifer Stocksdale, Jenna C. Glatzer, Jacqueline T. Pham, Ishrat Ahmed, Qi Peng, Harsh Wadhwa, Olga Pletnikova, Juan C. Troncoso, Wenzhen Duan, Solomon H. Snyder, Laura P. W. Ranum, Leslie M. Thompson, Thomas E. Lloyd, Christopher A. Ross, Jeffrey D. Rothstein
Review
Clinical Neurology
Sarah H. Berth, Thomas E. Lloyd
CURRENT TREATMENT OPTIONS IN NEUROLOGY
(2020)
Article
Multidisciplinary Sciences
Brett A. McCray, Erika Diehl, Jeremy M. Sullivan, William H. Aisenberg, Nicholas W. Zaccor, Alexander R. Lau, Dominick J. Rich, Benedikt Goretzki, Ute A. Hellmich, Thomas E. Lloyd, Charlotte J. Sumner
Summary: TRPV4 interacts with RhoA, affecting cell structure. The neuropathy effects of TRPV4 are related to incorrect binding with RhoA. Inhibition of RhoA can restore neurite length.
NATURE COMMUNICATIONS
(2021)
Article
Clinical Neurology
Christopher Grunseich, Nathan Sarkar, Joyce Lu, Mallory Owen, Alice Schindler, Peter A. Calabresi, Charlotte J. Sumner, Ricardo H. Roda, Vinay Chaudhry, Thomas E. Lloyd, Thomas O. Crawford, S. H. Subramony, Shin J. Oh, Perry Richardson, Kurenai Tanji, Justin Y. Kwan, Kenneth H. Fischbeck, Ami Mankodi
Summary: Integrating deep phenotyping, gene filter algorithms, and biological assays increased the diagnostic yield of exome sequencing, identified novel pathogenic variants, and extended the phenotypes of difficult-to-diagnose rare neurogenetic disorders in an outpatient clinic setting.
JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY
(2021)
Article
Cell Biology
Hyun Sung, Thomas E. Lloyd
Summary: Expression of expanded G(4)C(2) repeats differentially affects axonal transport of vesicular organelles and mitochondria in Drosophila models.
Article
Cell Biology
Sandeep Kumar Dubey, Kirstin Maulding, Hyun Sung, Thomas E. Lloyd
Summary: This study found that expression of GGGGCC repeats in Drosophila neurons leads to degradation of nucleoporins and this process is mediated by the Vps4 ATPase and the ESCRT-III complex, revealing a mechanism for nuclear pore complex dysfunction in neurodegenerative diseases.
Article
Cell Biology
Hyun Sung, Thomas E. Lloyd
Summary: Macroautophagy is crucial for eliminating protein aggregates and damaged organelles, and its dysregulation is implicated in neurodegenerative diseases like ALS and FTD. The expansion of G4C2 repeats in the C9orf72 gene disrupts autophagosome formation, highlighting the importance of dynamic ER tubules.
Review
Medicine, Research & Experimental
Sarah H. Berth, Thomas E. Lloyd
Summary: Neurons heavily depend on axonal transport for their health due to their compartmentalization. Axonal transport is essential for delivering newly synthesized macromolecules and organelles from the cell body to the synapse (anterograde transport) and for the retrograde delivery of signaling endosomes and autophagosomes for degradation. Dysfunction in axonal transport is an early event in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, hereditary spastic paraplegia, amyotrophic lateral sclerosis, and Charcot-Marie-Tooth disease. This article provides an overview of the mechanisms regulating axonal transport, discusses their disruption in various neurodegenerative diseases, and explores therapeutic approaches targeting axonal transport.
JOURNAL OF CLINICAL INVESTIGATION
(2023)
Article
Clinical Neurology
Anne-Katrin Guettsches, Stefen Brady, Kathryn Krause, Alexandra Maerkens, Julian Uszkoreit, Martin Eisenacher, Anja Schreiner, Sara Galozzi, Janine Mertens-Rill, Martin Tegenthoff, Janice L. Holton, Matthew B. Harms, Thomas E. Lloyd, Matthias Vorgerd, Conrad C. Weihl, Katrin Marcus, Rudolf A. Kley
ANNALS OF NEUROLOGY
(2017)