Review
Cell Biology
Xinwa Jiang, Ariana Gatt, Tammaryn Lashley
Summary: Frontotemporal dementia (FTD) is the second most common form of early-onset dementia, characterized by behavioral, executive, and/or language impairment. Frontotemporal lobar degeneration (FTLD) is the main cause of FTD and is associated with the abnormal accumulation of proteins like tau, TAR DNA-binding protein 43 (TDP-43), and fused in sarcoma (FUS). Recent studies have expanded the exploration of the relationship between other heterogeneous ribonucleic acid proteins (hnRNPs) and FTLD pathology, revealing the association between hnRNP abnormalities and FTLD. These findings highlight the important role of multiple hnRNPs in the development of FTLD and suggest the need for further research on this protein family.
Article
Multidisciplinary Sciences
Jelena Scekic-Zahirovic, Inmaculada Sanjuan-Ruiz, Vanessa Kan, Salim Megat, Pierre De Rossi, Stephane Dieterle, Raphaelle Cassel, Marguerite Jamet, Pascal Kessler, Diana Wiesner, Laura Tzeplaeff, Valerie Demais, Sonu Sahadevan, Katharina M. Hembach, Hans-Peter Muller, Gina Picchiarelli, Nibha Mishra, Stefano Antonucci, Sylvie Dirrig-Grosch, Jan Kassubek, Volker Rasche, Albert Ludolph, Anne-Laurence Boutillier, Francesco Roselli, Magdalini Polymenidou, Clotilde Lagier-Tourenne, Sabine Liebscher, Luc Dupuis
Summary: Mutations in the RNA binding protein FUS are associated with ALS. Here the authors show that in FUS knock-in mice there is a progressive increase in neuronal activity in the frontal cortex which is associated with altered synaptic gene expression.
NATURE COMMUNICATIONS
(2021)
Review
Clinical Neurology
Arenn F. Carlos, Keith A. Josephs
Summary: This paper reviews how FTLD-TDP was established and defined clinically and neuropathologically throughout the past century.
JOURNAL OF NEUROLOGY
(2022)
Article
Clinical Neurology
Tingting Zhang, Tuancheng Feng, Kenton Wu, Jennifer Guo, Alissa L. Nana, Guang Yang, William W. Seeley, Fenghua Hu
Summary: Heterozygous mutations in the GRN gene result in PGRN haploinsufficiency, leading to FTLD. PGRN deficiency also causes NCL and is associated with AD and PD. This study reveals that PGRN deficiency leads to sex-dependent myelination defects, with male mice showing more severe demyelination. Microglial proliferation and activation are exacerbated in male PGRN-deficient mice, and sustained microglial activation and remyelination defects are observed in both male and female PGRN-deficient mice. Specific ablation of PGRN in microglia confirms its role in these phenotypes. Accumulation of lipid droplets in microglia is specific to male PGRN-deficient mice. RNA-seq analysis and mitochondrial function assays reveal differences in oxidative phosphorylation between male and female microglia under PGRN deficiency. Similar myelination defects and lipid droplet accumulation are observed in FTLD patients with GRN mutations. These findings highlight the importance of PGRN in regulating microglial function and myelination.
ACTA NEUROPATHOLOGICA
(2023)
Review
Neurosciences
Hulya Ulugut, Anke A. Dijkstra, Marta Scarioni, Netherlands Brain Bank, Frederik Barkhof, Philip Scheltens, Annemieke J. M. Rozemuller, Yolande A. L. Pijnenburg
Summary: Despite being considered a right-sided variant of svPPA, rtvFTD may demonstrate either frontotemporal or temporal evolution. The most common underlying pathology is FTLD-TDP type C, but other pathologies such as Tau-MAPT and FTLD-TDP type A and B are also present in a significant percentage of rtvFTD cases. Additionally, motor neuron or corticospinal tract degeneration was observed in a portion of rtvFTD patients.
ACTA NEUROPATHOLOGICA COMMUNICATIONS
(2021)
Article
Clinical Neurology
Alexander Bampton, Ariana Gatt, Jack Humphrey, Sara Cappelli, Dipanjan Bhattacharya, Sandrine Foti, Anna-Leigh Brown, Yasmine Asi, Yi Hua Low, Marco Foiani, Towfique Raj, Emanuele Buratti, Pietro Fratta, Tammaryn Lashley
Summary: Heterogeneous nuclear ribonucleoproteins (HnRNPs) play crucial roles in nucleic acid metabolism, with HnRNP K mislocalisation in neurodegenerative diseases such as frontotemporal lobar degeneration and aging being associated with widespread splicing changes.
ACTA NEUROPATHOLOGICA
(2021)
Article
Neurosciences
Tingting Zhang, Huan Du, Mariela Nunez Santos, Xiaochun Wu, Mitchell D. Pagan, Lianne Jillian Trigiani, Nozomi Nishimura, Thomas Reinheckel, Fenghua Hu
Summary: This study generated and characterized antibodies specific to each granulin peptide and found that the levels of individual granulin peptides are differently regulated in different tissues. The study also revealed variations in the levels of PGRN and granulin peptides in different brain regions, and showed that the changes in granulin A corresponded to stroke but not demyelination. Furthermore, deficiency of lysosomal proteases and prosaposin affected the ratios between individual granulin peptides.
MOLECULAR NEURODEGENERATION
(2022)
Article
Chemistry, Multidisciplinary
Miriam Linsenmeier, Lenka Faltova, Chiara Morelli, Umberto Capasso Palmiero, Charlotte Seiffert, Andreas M. Kuffner, Dorothea Pinotsi, Jiangtao Zhou, Raffaele Mezzenga, Paolo Arosio
Summary: This study analyzes the amyloid formation mediated by hnRNPA1 and reveals that phase separation and fibrillization are connected but distinct processes. The study also shows that fibril formation is promoted at the interface of the condensates and can be inhibited by coating the interface with surfactant molecules.
Article
Clinical Neurology
Silvia Porta, Yan Xu, Tagan Lehr, Bin Zhang, Emily Meymand, Modupe Olufemi, Anna Stieber, Edward B. Lee, John Q. Trojanowski, Virginia M. -Y. Lee
Summary: This study demonstrates the presence of distinct TDP-43 strains in the brains of different FTLD-TDP subtypes with specific seeding and spreading properties in experimental animal models.
NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY
(2021)
Article
Clinical Neurology
Ernesto Garcia-Roldan, Eloy Rivas-Infante, Manuel Medina-Rodriguez, Jose Enrique Arriola-Infante, Silvia Rodrigo-Herrero, Carmen Paradas, Alberto Rabano-Gutierrez, Emilio Franco-Macias
Summary: This article describes a case of a 37-year-old male patient with rapidly progressive decline, motor symptoms, and behavioral changes. Laboratory and imaging findings were normal, but autopsy revealed severe frontotemporal atrophy and specific basophilic inclusions consistent with BIBD.
Article
Clinical Neurology
John L. Robinson, Sharon X. Xie, Daniel R. Baer, EunRan Suh, Vivianna M. Van Deerlin, Nicholas J. Loh, David J. Irwin, Corey T. McMillan, David A. Wolk, Alice Chen-Plotkin, Daniel Weintraub, Theresa Schuck, Virginia M. Y. Lee, John Q. Trojanowski, Edward B. Lee
Summary: In this retrospective study, the incidence of 10 pathologies in neurodegenerative disease (ND) and normal aging was examined, with up to seven pathologies observed concurrently resulting in 161 different combinations. The presence of multiple additive pathologies was associated with factors such as longer disease duration, clinical dementia, older age, and APOE e4 status.
Article
Clinical Neurology
Paolo Reho, Shunsuke Koga, Zalak Shah, Ruth Chia, Rosa Rademakers, Clifton L. Dalgard, Bradley F. Boeve, Thomas G. Beach, Dennis W. Dickson, Owen A. Ross, Sonja W. Scholz
Summary: This study aimed to evaluate pathogenic variants in GRN among Lewy body dementia (LBD) patients and found an enrichment of GRN loss-of-function mutations in the cases.
MOVEMENT DISORDERS
(2022)
Article
Clinical Neurology
Takashi Kurashige, Hiroyuki Morino, Tomomi Murao, Yuishin Izumi, Tomohito Sugiura, Kazuya Kuraoka, Hideshi Kawakami, Tsuyoshi Torii, Hirofumi Maruyama
Summary: The study aims to identify and characterize the histopathology of peripheral axons in the skeletal muscle of patients with ALS. The results suggest that axonal pTDP-43 accumulations may be characteristic for patients with ALS, and it could be a potential novel diagnostic biomarker for ALS.
Review
Cell Biology
Rebekka Kuhn, Aayushi Mahajan, Peter Canoll, Gunnar Hargus
Summary: Neurodegenerative dementias, including frontotemporal dementia, affect over 40 million people worldwide. The accumulation of tau protein in neurons and glial cells is a key feature of FTD, for which there is currently no cure. Research focuses on understanding the underlying mechanisms and potential therapeutic targets in these diseases.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Article
Multidisciplinary Sciences
Lisa Streit, Timo Kuhn, Thomas Vomhof, Verena Bopp, Albert C. Ludolph, Jochen H. Weishaupt, J. Christof M. Gebhardt, Jens Michaelis, Karin M. Danzer
Summary: The study revealed that TDP-43 mobility decreases under stress conditions, impacting its aggregation. Besides reduced mobility within stress granules, stress also leads to a decrease in TDP-43 mobility in the cytoplasm and nucleus, with recovery of mobility upon stress removal.
NATURE COMMUNICATIONS
(2022)
Article
Clinical Neurology
D. Hansen, H. Ling, T. Lashley, J. A. Foley, C. Strand, T. M. Eid, J. L. Holton, T. T. Warner
Summary: This study identified prominent concurrent cerebral amyloid angiopathy (CAA) as a pathological substrate of DLB and found that DLB has more severe CAA and faster disease progression compared to PDD. The absence of dyskinesia in DLB is linked to lower lifetime cumulative dose of levodopa than PDD.
NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY
(2021)
Article
Clinical Neurology
Rahul Sidhu, Ariana Gatt, Pietro Fratta, Tammaryn Lashley, Alexander Bampton
Summary: This study reveals that nuclear depletion and cytoplasmic mislocalisation of hnRNP K are common neuropathological features in FTLD and elderly control brain. Furthermore, the dentate nucleus of the cerebellum is also vulnerable to hnRNP K mislocalisation. The findings suggest that hnRNP K dysfunction may have broader relevance to neurodegeneration and ageing.
NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY
(2022)
Article
Clinical Neurology
Priya Gami-Patel, Marta Scarioni, Femke H. Bouwman, Baayla D. C. Boon, John C. van Swieten, Netherlands Brain Bank, Annemieke J. M. Rozemuller, August B. Smit, Yolande A. L. Pijnenburg, Jeroen J. M. Hoozemans, Anke A. Dijkstra
Summary: This study investigates the vulnerability of von Economo neurons (VENs) and GABA receptor subunit theta (GABRQ)-expressing neurons in different forms of frontotemporal dementia (FTD) and their association with behavioral symptoms. The results suggest that the loss of VENs and GABRQ-expressing neurons is linked to TDP43 and FUS pathology in FTD, and may play a key role in modulating behavior.
NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY
(2022)
Meeting Abstract
Biochemistry & Molecular Biology
Agueda Rostagno, Miguel Calero, Janice Holton, Tamas Revesz, Tammaryn Lashley, Jorge Ghiso
Meeting Abstract
Biochemistry & Molecular Biology
Jorge Ghiso, Erwin Cabrera, Tammaryn Lashley, Agueda Rostagno
Editorial Material
Neurosciences
Alexis Moscoso, Melissa C. Wren, Tammaryn Lashley, Erik Arstad, Melissa E. Murray, Nick C. Fox, Kerstin Sander, Michael Scholl
MOLECULAR NEURODEGENERATION
(2022)
Article
Multidisciplinary Sciences
Manuel Schweighauser, Diana Arseni, Melissa Huang, Sofia Lovestam, Yang Shi, Yang Yang, Wenjuan Zhang, Abhay Kotecha, Holly J. Garringer, Ruben Vidal, Grace Hallinan, Kathy L. Newell, Airi Tarutani, Shigeo Murayama, Masayuki Miyazaki, Yuko Saito, Mari Yoshida, Kazuko Hasegawa, Tammaryn Lashley, Tamas Revesz, Gabor G. Kovacs, John van Swieten, Masaki Takao, Masato Hasegawa, Bernardino Ghetti, Benjamin Falcon, Alexey G. Murzin, Michel Goedert, Sjors H. W. Scheres, Maria Grazia Spillantini
Summary: The study found that TMEM106B protein forms amyloid filaments in the brains of patients with various neurodegenerative diseases. The structures of TMEM106B filaments differ in different brain regions and do not show clear associations with specific diseases. The presence of TMEM106B filaments in the brains of older individuals suggests an age-dependent formation pattern, which is not observed in younger individuals with normal neurology.
Article
Biochemistry & Molecular Biology
Wojciech Michno, Srinivas Koutarapu, Rafael Camacho, Christina Toomey, Katie Stringer, Karolina Minta, Junyue Ge, Durga Jha, Julia Fernandez-Rodriguez, Gunnar Brinkmalm, Henrik Zetterberg, Kaj Blennow, Natalie S. Ryan, Tammaryn Lashley, Jorg Hanrieder
Summary: Familial British dementia (FBD) and familial Danish dementia (FDD) are autosomal dominant forms of dementia caused by mutations in the ITM2B gene. The amyloid pathology in FBD/FDD manifests in the microvasculature, with FDD also showing co-aggregation with A beta. Using mass spectrometry imaging and fluorescence probes, researchers found differences in amyloid peptide species between FBD and FDD, providing new insights into the pathogenesis of vascular dementias.
JOURNAL OF NEUROCHEMISTRY
(2022)
Article
Clinical Neurology
Megha Murthy, Gemma Shireby, Yasuo Miki, Emmanuelle Vire, Tammaryn Lashley, Thomas T. Warner, Jonathan Mill, Conceicao Bettencourt
Summary: This study investigated the epigenetic aging in white matter for the first time, and found that oligodendrocyte proportions positively influence epigenetic age acceleration.
NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY
(2023)
Article
Neurosciences
Ileana Lorenzini, Eric Alsop, Jennifer Levy, Lauren M. Gittings, Deepti Lall, Benjamin E. Rabichow, Stephen Moore, Ryan Pevey, Lynette M. Bustos, Camelia Burciu, Divya Bhatia, Mo Singer, Justin Saul, Amanda McQuade, Makis Tzioras, Thomas A. Mota, Amber Logemann, Jamie Rose, Sandra Almeida, Fen-Biao Gao, Michael Marks, Christopher J. Donnelly, Elizabeth Hutchins, Shu-Ting Hung, Justin Ichida, Robert Bowser, Tara Spires-Jones, Mathew Blurton-Jones, Tania F. Gendron, Robert H. Baloh, Kendall Van Keuren-Jensen, Rita Sattler
Summary: In this study, researchers investigate the role of non-neuronal cells, specifically microglia, in C9orf72 amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). They find that iPSC-derived microglia from C9orf72 ALS/FTD patients exhibit pathological features and perform similar functions as healthy control microglia. Transcriptomic analysis reveals selective transcriptional changes related to neuroinflammation and neurodegeneration in diseased microglia. The findings suggest that a diseased microenvironment is required to induce phenotypic changes in microglia and the associated neuronal dysfunction in C9orf72 ALS/FTD.
FRONTIERS IN CELLULAR NEUROSCIENCE
(2023)
Review
Cell Biology
Xinwa Jiang, Ariana Gatt, Tammaryn Lashley
Summary: Frontotemporal dementia (FTD) is the second most common form of early-onset dementia, characterized by behavioral, executive, and/or language impairment. Frontotemporal lobar degeneration (FTLD) is the main cause of FTD and is associated with the abnormal accumulation of proteins like tau, TAR DNA-binding protein 43 (TDP-43), and fused in sarcoma (FUS). Recent studies have expanded the exploration of the relationship between other heterogeneous ribonucleic acid proteins (hnRNPs) and FTLD pathology, revealing the association between hnRNP abnormalities and FTLD. These findings highlight the important role of multiple hnRNPs in the development of FTLD and suggest the need for further research on this protein family.
Article
Clinical Neurology
Lauren M. Gittings, Eric B. Alsop, Jerry Antone, Mo Singer, Timothy G. Whitsett, Rita Sattler, Kendall Van Keuren-Jensen
Summary: Recent study found that the loss of TDP-43 function leads to the inclusion of cryptic exons (CE) in RNA transcript targets, and these CE-containing transcripts were detected in the sensory and visual cortices of C9ORF72-related ALS and FTD patients. In C9ORF72-FTD patients, a cluster of excitatory neurons containing CEs showed transcriptomic similarities to von Economo neurons. Dysregulated metabolic processes were found in CE-containing neurons through gene expression and pathway analysis. These findings provide novel insights into the transcriptomic changes in neurons vulnerable to TDP-43 pathology.
ACTA NEUROPATHOLOGICA
(2023)
Article
Cell Biology
Megha Murthy, Patrizia Rizzu, Peter Heutink, Jonathan Mill, Tammaryn Lashley, Conceicao Bettencourt
Summary: Frontotemporal lobar degeneration (FTLD) is a group of disorders characterized by degeneration of the frontal and temporal lobes. Recent research has shown that significant differential DNA methylation in DLX1 and OTUD4 loci may contribute to FTLD. This study found that there is accelerated epigenetic aging in FTLD patients compared to controls, particularly in peripheral blood. The findings suggest that increased epigenetic age acceleration in peripheral blood could be an indicator for FTLD subtypes like progressive supranuclear palsy (PSP) and frontotemporal dementia (FTD).
Meeting Abstract
Clinical Neurology
Ariana Gatt, Alex Bampton, Jack Humphrey, Sara Cappelli, Emanuele Buratti, Pietro Fratta, Tammaryn Lashley
NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY
(2021)
Article
Clinical Neurology
Eduardo de Pablo-Fernandez, Belen Gonzalez-Herrero, Debora Cerdan Santacruz, Martin N. Rossor, Jonathan M. Schott, Tammaryn Lashley, Janice L. Holton, Nick C. Fox, Tamas Revesz, Jason D. Warren, Zane Jaunmuktane, Jonathan D. Rohrer, Thomas T. Warner
Summary: This study provides a detailed description of movement disorders in FTLD patients, finding that parkinsonism and corticobasal syndrome are common syndromes associated with FTLD, with parkinsonism presenting more often in the late stages of the disease and corticobasal syndrome as an initial symptom. The study also suggests that there is a complex pathophysiology involving structures beyond the presynaptic striatonigral system in FTLD-related movement disorders.
MOVEMENT DISORDERS
(2021)
