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
Genetics & Heredity
Heleen M. van't Spijker, Sandra Almeida
Summary: A hexanucleotide repeat expansion in the C9ORF72 gene is strongly associated with ALS and FTD. Research has focused on understanding the pathogenesis of these diseases and identifying potential therapeutic targets, particularly the toxic DPR proteins. The synthesis of DPR proteins from RNAs with repeat expansions is still not fully understood. This review summarizes our current knowledge of the translation mechanisms involved and discusses how this understanding could lead to effective preventative therapies for C9ORF72 ALS-FTD.
Article
Biology
Yoshifumi Sonobe, Soojin Lee, Gopinath Krishnan, Yuanzheng Gu, Deborah Y. Kwon, Fen-Biao Gao, Raymond P. Roos, Paschalis Kratsios
Summary: A hexanucleotide repeat expansion in C9ORF72 is the most common genetic cause of ALS and FTD. Translation of DPR proteins depends on non-canonical initiation codons, but the study found that two antisense DPRs, poly-PR and poly-PG, are translated using canonical AUG codons.
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
Cell Biology
Sarah Pickles, Desiree Zanetti Alepuz, Yuka Koike, Mei Yue, Jimei Tong, Pinghu Liu, Yugui Zhou, Karen Jansen-West, Lillian M. M. Daughrity, Yuping Song, Michael DeTure, Bjoern Oskarsson, Neill R. R. Graff-Radford, Bradley F. F. Boeve, Ronald C. C. Petersen, Keith A. A. Josephs, Dennis W. W. Dickson, Michael E. E. Ward, Lijin Dong, Mercedes Prudencio, Casey N. N. Cook, Leonard Petrucelli
Summary: The limited treatments for neurodegenerative diseases such as FTD and ALS highlight the need for better understanding of their mechanisms and the development of disease-relevant models. Researchers have generated a novel CRISPRi knockin mouse to overcome the limitations of conventional knockout and transgenic mice. This model has been validated by confirming the reduced levels of STMN2 protein in FTD and has the potential for further research in understanding gene function and neurodegenerative diseases.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2023)
Review
Cell Biology
Jimmy Beckers, Arun Kumar Tharkeshwar, Philip Van Damme
Summary: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two distinct classes of neurodegenerative disorders, sharing genetic, cellular, and molecular features. Common features include hexanucleotide repeat expansions in the C9orf72 gene and accumulation of toxic protein aggregates in affected individuals' nervous systems, potentially caused by toxic gain of function from transcribed HRE RNA or DPRs. Furthermore, alterations in protein homeostasis are suggested as a root cause of disease pathogenesis.
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
Clinical Neurology
Claudia S. Bauer, Rebecca N. Cohen, Francesca Sironi, Matthew R. Livesey, Thomas H. Gillingwater, J. Robin Highley, Daniel J. Fillingham, Ian Coldicott, Emma F. Smith, Yolanda B. Gibson, Christopher P. Webster, Andrew J. Grierson, Caterina Bendotti, Kurt J. De Vos
Summary: A GGGGCC hexanucleotide repeat expansion in the C9ORF72 gene is the main genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. This study shows that C9orf72 protein interacts with the synapsin family of synaptic vesicle proteins, and C9orf72 deficiency reduces the number of excitatory synapses and synapsin levels, leading to synaptic dysfunction.
ACTA NEUROPATHOLOGICA
(2022)
Article
Medicine, Research & Experimental
Yuanjing Liu, Amy Andreucci, Naoki Iwamoto, Yuan Yin, Hailin Yang, Fangjun Liu, Alexey Bulychev, Xiao Shelley Hu, Xuena Lin, Sarah Lamore, Saurabh Patil, Susovan Mohapatra, Erin Purcell-Estabrook, Kristin Taborn, Elena Dale, Chandra Vargeese
Summary: The researchers report a stereopure antisense oligonucleotide, WVE-004, that selectively reduces repeat-containing transcripts in patients and mice with C9orf72-repeat expansion. They observed a decrease in pathological biomarkers and preservation of healthy protein expression. These findings support the development of WVE-004 as a potential treatment for C9orf72-associated diseases.
MOLECULAR THERAPY-NUCLEIC ACIDS
(2022)
Article
Neurosciences
Maria-Belen Lopez-Herdoiza, Stephanie Bauche, Baptiste Wilmet, Caroline Le Duigou, Delphine Roussel, Magali Frah, Jonas Beal, Gabin Devely, Susana Boluda, Petra Frick, Delphine Bouteiller, Sebastien Dussaud, Pierre Guillabert, Carine Dalle, Magali Dumont, Agnes Camuzat, Dario Saracino, Mathieu Barbier, Gaelle Bruneteau, Phillippe Ravassard, Manuela Neumann, Sophie Nicole, Isabelle Le Ber, Alexis Brice, Morwena Latouche
Summary: The GGGGCC intronic repeat expansion within C9ORF72 is a common genetic cause of ALS and FTD. This mutation leads to toxic gain of function through accumulation of expanded RNA foci and aggregation of abnormally translated dipeptide repeat proteins, as well as loss of function due to impaired transcription of C9ORF72. Knockdown mice with decreased C9ORF72 showed abnormalities in the autophagy/lysosomal pathway, cytoplasmic accumulation of TDP-43, decreased synaptic density in the cortex, and developed FTD-like behavioral deficits and mild motor phenotypes at a later stage. These findings indicate that partial loss of function of C9ORF72 contributes to the damaging events leading to C9-FTD/ALS.
FRONTIERS IN CELLULAR NEUROSCIENCE
(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)
Review
Neurosciences
Layla T. Ghaffari, Davide Trotti, Aaron R. Haeusler, Brigid K. Jensen
Summary: ALS is a progressive neurodegenerative disease with heterogeneous clinical manifestations and lack of effective treatment. Cortical hyper-excitability is observed early in the disease and is associated with nucleotide repeat expansion in the C9ORF72 gene. ALS and FTD are part of a disease spectrum, both characterized by synaptic dysfunction.
FRONTIERS IN MOLECULAR NEUROSCIENCE
(2022)
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
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
Neurosciences
Alexander Schmitz, Joao Pinheiro Marques, Irina Oertig, Niran Maharjan, Smita Saxena
Summary: The most common genetic cause of ALS and FTD is a hexanucleotide expansion in the C9ORF72 gene, which leads to various disease pathologies. Different forms of DPRs have different contributions to disease pathology, and recent advances in neuropathology and cellular studies have provided clues to understand their effects better.
FRONTIERS IN CELLULAR NEUROSCIENCE
(2021)
Article
Neurosciences
Anke A. Dijkstra, Li-Chun Lin, Alissa L. Nana, Stephanie E. Gaus, William W. Seeley
Article
Clinical Neurology
Ethan G. Geier, Mathieu Bourdenx, Nadia J. Storm, J. Nicholas Cochran, Daniel W. Sirkis, Ji-Hye Hwang, Luke W. Bonham, Eliana Marisa Ramos, Antonio Diaz, Victoria Van Berlo, Deepika Dokuru, Alissa L. Nana, Anna Karydas, Maureen E. Balestra, Yadong Huang, Silvia P. Russo, Salvatore Spina, Lea T. Grinberg, William W. Seeley, Richard M. Myers, Bruce L. Miller, Giovanni Coppola, Suzee E. Lee, Ana Maria Cuervo, Jennifer S. Yokoyama
ACTA NEUROPATHOLOGICA
(2019)
Article
Clinical Neurology
Alissa L. Nana, Manu Sidhu, Stephanie E. Gaus, Ji-Hye L. Hwang, Libo Li, Youngsoon Park, Eun-Joo Kim, Lorenzo Pasquini, Isabel E. Allen, Katherine P. Rankin, Gianina Toller, Joel H. Kramer, Daniel H. Geschwind, Giovanni Coppola, Eric J. Huang, Lea T. Grinberg, Bruce L. Miller, William W. Seeley
ACTA NEUROPATHOLOGICA
(2019)
Article
Clinical Neurology
Salvatore Spina, Jesse A. Brown, Jersey Deng, Raquel C. Gardner, Alissa L. Nana, Ji-Hye L. Hwang, Stephanie E. Gaus, Eric J. Huang, Joel H. Kramer, Howie J. Rosen, John Kornak, John Neuhaus, Bruce L. Miller, Lea T. Grinberg, Adam L. Boxer, William W. Seeley
Article
Neurosciences
So Yoen Choi, Rodrigo Lopez-Gonzalez, Gopinath Krishnan, Hannah L. Phillips, Alissa Nana Li, William W. Seeley, Wei-Dong Yao, Sandra Almeida, Fen-Biao Gao
NATURE NEUROSCIENCE
(2019)
Article
Neurosciences
Niraj M. Shanbhag, Mark D. Evans, Wenjie Mao, Alissa L. Nana, William W. Seeley, Anthony Adame, Robert A. Rissman, Eliezer Masliah, Lennart Mucke
ACTA NEUROPATHOLOGICA COMMUNICATIONS
(2019)
Article
Clinical Neurology
Eun-Joo Kim, Ji-Hye L. Hwang, Stephanie E. Gaus, Alissa L. Nana, Jersey Deng, Jesse A. Brown, Salvatore Spina, Myung Jun Lee, Eliana Marisa Ramos, Lea T. Grinberg, Joel H. Kramer, Adam L. Boxer, Maria Luisa Gorno-Tempini, Howard J. Rosen, Bruce L. Miller, William W. Seeley
ACTA NEUROPATHOLOGICA
(2020)
Letter
Clinical Neurology
Paul J. Sampognaro, Sarat C. Vatsavayai, Celica G. Cosme, Ji-Hye L. Hwang, Amber Nolan, Eric J. Huang, William W. Seeley, Mary G. De May
ACTA NEUROPATHOLOGICA
(2019)
Article
Neurosciences
Li-Chun Lin, Alissa L. Nana, Mackenzie Hepker, Ji-Hye Lee Hwang, Stephanie E. Gaus, Salvatore Spina, Celica G. Cosme, Li Gan, Lea T. Grinberg, Daniel H. Geschwind, Giovanni Coppola, Howard J. Rosen, Bruce L. Miller, William W. Seeley
ACTA NEUROPATHOLOGICA COMMUNICATIONS
(2019)
Article
Neurosciences
Andrew E. Arrant, Jonathan R. Roth, Nicholas R. Boyle, Shreya N. Kashyap, Madelyn Q. Hoffmann, Charles F. Murchison, Eliana Marisa Ramos, Alissa L. Nana, Salvatore Spina, Lea T. Grinberg, Bruce L. Miller, William W. Seeley, Erik D. Roberson
ACTA NEUROPATHOLOGICA COMMUNICATIONS
(2019)
Article
Multidisciplinary Sciences
Sebastian Boland, Sharan Swarup, Yohannes A. Ambaw, Pedro C. Malia, Ruth C. Richards, Alexander W. Fischer, Shubham Singh, Geetika Aggarwal, Salvatore Spina, Alissa L. Nana, Lea T. Grinberg, William W. Seeley, Michal A. Surma, Christian Klose, Joao A. Paulo, Andrew D. Nguyen, J. Wade Harper, Tobias C. Walther, Robert V. Farese
Summary: The absence of progranulin (PGRN) leads to the accumulation of gangliosides in brain cells and tissues, causing neurodegenerative diseases.
NATURE COMMUNICATIONS
(2022)
Article
Neurosciences
Kristina D. Micheva, Edward F. Chang, Alissa L. Nana, William W. Seeley, Jonathan T. Ting, Charles Cobbs, Ed Lein, Stephen J. Smith, Richard J. Weinberg, Daniel V. Madison
Article
Clinical Neurology
David C. Perry, Jesse A. Brown, Katherine L. Possin, Samir Datta, Andrew Trujillo, Anneliese Radke, Anna Karydas, John Kornak, Ana C. Sias, Gil D. Rabinovici, Maria Luisa Gorno-Tempini, Adam L. Boxer, Mary De May, Katherine P. Rankin, Virginia E. Sturm, Suzee E. Lee, Brandy R. Matthews, Aimee W. Kao, Keith A. Vossel, Maria Carmela Tartaglia, Zachary A. Miller, Sang Won Seo, Manu Sidhu, Stephanie E. Gaus, Alissa L. Nana, Jose Norberto S. Vargas, Ji-Hye L. Hwang, Rik Ossenkoppele, Alainna B. Brown, Eric J. Huang, Giovanni Coppola, Howard J. Rosen, Daniel Geschwind, John Q. Trojanowski, Lea T. Grinberg, Joel H. Kramer, Bruce L. Miller, William W. Seeley