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
Biology
Yuzo Fujino, Morio Ueyama, Taro Ishiguro, Daisaku Ozawa, Hayato Ito, Toshihiko Sugiki, Asako Murata, Akira Ishiguro, Tania Gendron, Kohji Mori, Eiichi Tokuda, Tomoya Taminato, Takuya Konno, Akihide Koyama, Yuya Kawabe, Toshihide Takeuchi, Yoshiaki Furukawa, Toshimichi Fujiwara, Manabu Ikeda, Toshiki Mizuno, Hideki Mochizuki, Hidehiro Mizusawa, Keiji Wada, Kinya Ishikawa, Osamu Onodera, Kazuhiko Nakatani, Leonard Petrucelli, Hideki Taguchi, Yoshitaka Nagai
Summary: Abnormal expansions of GGGGCC repeat sequence in the C9orf72 gene cause familial amyotrophic lateral sclerosis and frontotemporal dementia. Noncanonical repeat-associated non-AUG (RAN) translation of the expanded repeat sequence generates dipeptide repeat proteins (DPRs). The RNA-binding protein (RBP) FUS suppresses RAN translation and neurodegeneration by binding to and modulating the G-quadruplex structure of GGGGCC repeat RNA.
Article
Clinical Neurology
Harper S. Kim, John Son, Donghwan Lee, Joy Tsai, Danny Wang, E. Sandra Chocron, Seongwoo Jeong, Pamela Kittrell, Charles F. Murchison, Richard E. Kennedy, Alejandro Tobon, Carlayne E. Jackson, Andrew M. Pickering
Summary: In patients with ALS, different subtypes (sALS and bALS) show different dysbiosis patterns. sALS patients primarily exhibit gut dysbiosis, while bALS patients primarily exhibit oral dysbiosis. For sALS patients, gut dysbiosis is associated with microbial translocation and symptom severity, while for bALS patients, oral dysbiosis is associated with microbial translocation and disease severity. Both subtypes display oral motor deficits, but only in bALS is oral dysbiosis correlated with severity of oral motor deficits.
Review
Neurosciences
Philip Mcgoldrick, Janice Robertson
Summary: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two adult-onset neurodegenerative diseases that share common genetic and pathological characteristics. A mutation in the C9orf72 gene, characterized by a hexanucleotide repeat expansion, plays a significant role in both diseases. The abnormal nucleocytoplasmic transport system associated with this mutation is believed to contribute to the development and progression of ALS and FTD.
FRONTIERS IN CELLULAR NEUROSCIENCE
(2023)
Article
Neurosciences
M. Rebecca Glineburg, Yuan Zhang, Amy Krans, Elizabeth M. Tank, Sami J. Barmada, Peter K. Todd
Summary: A repeat-specific form of hybridization chain reaction (R-HCR) was developed as an alternative method for detecting repeat RNA foci in neurodegenerative disorders, exhibiting high specificity and sensitivity compared to fluorescence in situ hybridization (FISH). R-HCR was able to detect both nuclear and cytoplasmic foci in patient cells and could potentially track the behavior of repeat expansion mRNA in various disorders.
ACTA NEUROPATHOLOGICA COMMUNICATIONS
(2021)
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
Medicine, Research & Experimental
Indranil Malik, Yi-Ju Tseng, Shannon E. Wright, Kristina Zheng, Prithika Ramaiyer, Katelyn M. Green, Peter K. Todd
Summary: The study shows that CGG repeat RNA binding proteins play crucial roles in RAN translation and repeat toxicity, and inhibiting SRPK can alleviate toxicity in fruit flies and rodent neuron models.
EMBO MOLECULAR MEDICINE
(2021)
Article
Clinical Neurology
Jessica Mandrioli, Elisabetta Zucchi, Ilaria Martinelli, Laura Van der Most, Giulia Gianferrari, Cristina Moglia, Umberto Manera, Luca Solero, Rosario Vasta, Antonio Canosa, Maurizio Grassano, Maura Brunetti, Letizia Mazzini, Fabiola De Marchi, Cecilia Simonini, Nicola Fini, Rossella Tupler, Marco Vinceti, Adriano Chio, Andrea Calvo
Summary: This population-based cohort study identified clinical features, comorbidities, disease progression, and prognostic factors in ALS patients carrying C9ORF72 expansion. Compared to patients without mutations, C9 + ALS patients had a higher proportion of family history and frontotemporal dementia, as well as faster disease progression, shorter diagnostic delay, and earlier onset. However, when coexisting with thyroid disorders, C9 + ALS patients had a longer survival.
JOURNAL OF NEUROLOGY
(2023)
Article
Clinical Neurology
Giuseppe Borghero, Francesca Pili, Antonella Muroni, Tommaso Ercoli, Maria Ida Pateri, Silvy Pilotto, Alessandra Maccabeo, Giovanni Defazio
Summary: This study assessed the relationship between TARDBP and ALS progression/survival. The results showed that patients carrying TARDBP mutations had better survival/prognosis compared to C9orf72-positive and nmALS patients, and their disease progression was slower.
JOURNAL OF NEUROLOGY
(2023)
Review
Neurosciences
Agnes L. Nishimura, Natalia Arias
Summary: Amyotrophic Lateral Sclerosis (ALS) is a complex neurodegenerative disease caused by motor neuron degeneration. Loss of C9orf72 function and toxic effects of repeat expansions may contribute to the pathogenesis of ALS, leading to neurotransmission deficiencies.
FRONTIERS IN CELLULAR NEUROSCIENCE
(2021)
Article
Neurosciences
Indranil Malik, Yi-Ju Tseng, Clare M. Wieland, Katelyn M. Green, Kristina Zheng, Katyanne Calleja, Peter K. Todd
Summary: Neurodegeneration in FXTAS is caused by a CGG trinucleotide repeat expansion in FMR1, leading to the formation of stable secondary structures and toxic peptides through RAN translation. DAP5 knockdown can effectively suppress CGG repeat-associated toxicity and inhibit RAN translation. These findings suggest a potential role for DAP5 in modulating CGG repeat-associated toxicity.
NEUROBIOLOGY OF DISEASE
(2023)
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
Neuroimaging
Anna Nigri, Manera Umberto, Mario Stanziano, Stefania Ferraro, Davide Fedeli, Jean Paul Medina Carrion, Sara Palermo, Laura Lequio, Federica Denegri, Federica Agosta, Massimo Filippi, Maria Consuelo Valentini, Antonio Canosa, Andrea Calvo, Adriano Chio, Maria Grazia Bruzzone, Cristina Moglia
Summary: C9orf72 mutation carriers with different neurological phenotypes show cortical and subcortical atrophy in multiple brain regions, even in pre-symptomatic phases. This study found disease-specific patterns of thalamo-cortico-striatal atrophy and functional alterations in ALS patients with C9orf72 mutation. Importance rating: 8/10.
NEUROIMAGE-CLINICAL
(2023)
Article
Biochemistry & Molecular Biology
Jose Jimenez-Villegas, Janine Kirby, Ana Mata, Susana Cadenas, Martin R. Turner, Andrea Malaspina, Pamela J. Shaw, Antonio Cuadrado, Ana Rojo
Summary: The hexanucleotide expansion of the C9orf72 gene is associated with familial amyotrophic lateral sclerosis (ALS). This study found that the expression of redox-related genes was altered in leukocytes from C9orf72 ALS patients. Further experiments revealed that exposure to dipeptide repeat (DPR) toxicity decreased NRF2 protein levels, leading to increased superoxide levels and reduced cell survival. However, activation of NRF2 was able to restore cell viability and redox homeostasis. This suggests that NRF2 may be a potential target for precision medicine in treating ALS patients with C9orf72 expansion repeats.
Article
Multidisciplinary Sciences
Gopinath Krishnan, Denitza Raitcheva, Daniel Bartlett, Mercedes Prudencio, Diane M. McKenna-Yasek, Catherine Douthwright, Bjorn E. Oskarsson, Shafeeq Ladha, Oliver D. King, Sami J. Barmada, Timothy M. Miller, Robert Bowser, Jonathan K. Watts, Leonard Petrucelli, Robert H. Brown, Mark W. Kankel, Fen-Biao Gao
Summary: The GGGGCC repeat expansion in C9ORF72 is a common genetic cause of ALS and FTD, leading to the production of five DPR proteins. Sensitive assays have been developed to detect poly(GA) and poly(GR) levels in the CSF of C9ORF72 mutation carriers. The levels of these DPR proteins do not correlate with disease characteristics but decrease with ASO treatment, suggesting their potential as fluid-based biomarkers.
NATURE COMMUNICATIONS
(2022)
Review
Cell Biology
Jason P. Chua, Hortense De Calbiac, Edor Kabashi, Sami J. Barmada
Summary: Protein homeostasis mechanisms are crucial for maintaining the health of neurons and other cells in the central nervous system, while autophagy plays a key role in preventing and combating pathogenic insults that may lead to neurodegenerative diseases. However, the specific mechanisms underlying the neuroprotective role of autophagy, neuronal resistance to autophagy induction, and the effects of autophagy-impairing mutations on neurons are not fully understood. Additionally, the contribution of non-cell autonomous effects of autophagy dysfunction to ALS pathogenesis remains incompletely defined.
Article
Biochemistry & Molecular Biology
Yuan Zhang, M. Rebecca Glineburg, Venkatesha Basrur, Kevin Conlon, Shannon E. Wright, Amy Krans, Deborah A. Hall, Peter K. Todd
Summary: This study used mass spectrometry to detect signature fragments of FMRpolyG protein in patient samples, demonstrating that FMRpolyG is quantifiable in human samples. The study also found that RAN translation of FMR1 occurs through similar mechanisms, dependent on available initiation factors and cellular environment.
HUMAN MOLECULAR GENETICS
(2022)
Article
Biochemistry & Molecular Biology
Michael McMillan, Nicolas Gomez, Caroline Hsieh, Michael Bekier, Xingli Li, Roberto Miguez, Elizabeth M. H. Tank, Sami J. Barmada
Summary: RNA methylation at adenosine N6 (m6A) is a common RNA modification that affects RNA stability, transport, and translation. The study reveals that TDP43 recognizes m6A RNA and that RNA methylation plays a critical role in TDP43 binding and autoregulation. Extensive RNA hypermethylation is also observed in ALS spinal cord, which correlates with methylated TDP43 substrates.
Article
Neurosciences
Bilal Khalil, Deepak Chhangani, Melissa C. Wren, Courtney L. Smith, Jannifer H. Lee, Xingli Li, Christian Puttinger, Chih-Wei Tsai, Gael Fortin, Dmytro Morderer, Junli Gao, Feilin Liu, Chun Kim Lim, Jingjiao Chen, Ching-Chieh Chou, Cara L. Croft, Amanda M. Gleixner, Christopher J. Donnelly, Todd E. Golde, Leonard Petrucelli, Bjorn Oskarsson, Dennis W. Dickson, Ke Zhang, James Shorter, Shige H. Yoshimura, Sami J. Barmada, Diego E. Rincon-Limas, Wilfried Rossoll
Summary: The study found that members of the nuclear import receptor protein family can reduce the formation of pathological TDP-43 aggregates. Using KPNB1 as a model, it was discovered that its activity depends on the prion-like C-terminal region of TDP-43, mediating co-aggregation with nucleoporins such as Nup62. KPNB1 acts as a molecular chaperone in these co-aggregates, reversing the aberrant phase transition of Nup62 and TDP-43.
MOLECULAR NEURODEGENERATION
(2022)
Article
Multidisciplinary Sciences
Stephanie S. Sandoval-Pistorius, Julia E. Gerson, Nyjerus Liggans, Jaimie H. Ryou, Kulin Oak, Xingli Li, Keyshla Y. Negron-Rios, Svetlana Fischer, Henry Barsh, Emily V. Crowley, Mary E. Skinner, Lisa M. Sharkey, Sami J. Barmada, Henry L. Paulson
Summary: The key protein implicated in Parkinson's disease and other synucleinopathies is alpha-synuclein, especially its phosphorylated form at serine 129 (pS129). A protein quality control protein called Ubiquilin-2 (UBQLN2) is known to accumulate in synucleinopathies, and this study shows that UBQLN2 directly regulates alpha-synuclein, particularly pS129. The dysregulation of UBQLN2 in the disease may contribute to alpha-synuclein-mediated toxicity.
SCIENTIFIC REPORTS
(2023)
Article
Clinical Neurology
Pedro Ervilha Pereira, Nika Schuermans, Antoon Meylemans, Pontus LeBlanc, Lauren Versluys, Katie E. E. Copley, Jack D. D. Rubien, Christopher Altheimer, Myra Peetermans, Elke Debackere, Olivier Vanakker, Sandra Janssens, Jonathan Baets, Kristof Verhoeven, Martin Lammens, Sofie Symoens, Boel De Paepe, Sami J. J. Barmada, James Shorter, Jan L. L. De Bleecker, Elke Bogaert, Bart Dermaut
Summary: This study identified a TDP-43(p.Trp385IlefsTer10) mutation in a family, which led to the presence of TDP-43-positive inclusions in muscle cells and the development of autosomal dominant rimmed vacuole myopathy. The mutation was found to increase the aggregation propensity of TDP-43, but it was not associated with ALS and FTD.
ACTA NEUROPATHOLOGICA
(2023)
Article
Multidisciplinary Sciences
Ahmed M. Malik, Josephine J. Wu, Christie A. Gillies, Quinlan A. Doctrove, Xingli Li, Haoran Huang, Elizabeth H. M. Tank, Vikram G. Shakkottai, Sami Barmada
Summary: RNA-binding protein (RBP) dysfunction plays a fundamental role in amyotrophic lateral sclerosis (ALS) and related neuromuscular disorders. This study shows that activity-dependent processes regulate the levels and functions of the RBP Matrin 3 (MATR3). Glutamatergic activity drives MATR3 degradation, and mutations in MATR3 render it resistant to degradation, suggesting a link between activity-dependent MATR3 regulation and disease.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Review
Biology
Shannon E. Wright, Peter K. Todd
Summary: Over a third of the human genome consists of repetitive sequences, including more than a million short tandem repeats (STRs). While there is extensive research on the pathological consequences of repeat expansions causing syndromic human diseases, the potential native functions of STRs are often overlooked. This article summarizes the growing body of research on the normal biological functions of repetitive elements, with a focus on the roles of STRs in regulating gene expression. The authors propose reimagining the pathogenic consequences of repeat expansions as abnormalities in normal gene regulation and anticipate that future studies will uncover broader roles for STRs in neuronal function and as risk alleles for common human neurological diseases.
Editorial Material
Clinical Neurology
Megan Dykstra, Sami J. Barmada
Summary: This scientific commentary discusses Bodin et al.'s paper "Transactive response DNA-binding protein 43 is enriched at the centrosome in human cells" (https://doi.org/10.1093/brain/awad228).
Editorial Material
Clinical Neurology
Rita Sattler, Bryan J. Traynor, Janice Robertson, Ludo Van den Bosch, Sami J. Barmada, Clive N. Svendsen, Matthew D. Disney, Tania F. Gendron, Philip C. Wong, Martin R. Turner, Adam Boxer, Suma Babu, Michael Benatar, Michael Kurnellas, Jonathan D. Rohrer, Christopher J. Donnelly, Lynette M. Bustos, Kendall Van Keuren-Jensen, Penny A. Dacks, Marwan N. Sabbagh
Summary: The summit highlighted the role of the C9ORF72 gene in FTD and ALS, covering disease mechanisms, therapeutic strategies, and biomarkers. Collaborative efforts aimed to break down existing disease silos and proposed composite endpoints for evaluating treatments covering clinical symptoms.
NEUROLOGY AND THERAPY
(2023)
Meeting Abstract
Biotechnology & Applied Microbiology
B. C. Campbell, M. Bekier, A. Lettko, M. Zamatkesh, D. Lokhorst, S. Van der Sanden, A. Griffith, A. Georgiadis, B. Nguyen-Vu, M. During, A. Forbes, S. J. Barmada, C. F. Liu
HUMAN GENE THERAPY
(2022)
Meeting Abstract
Clinical Neurology
Jason P. Chua, Erin S. Kim, C. Stumpf Sarah, Luisa Aring, Young Ah-Seo, Sami J. Barmada, Valina L. Dawson, Ted M. Dawson
ANNALS OF NEUROLOGY
(2022)
Article
Cell Biology
Tania F. Gendron, Michael G. Heckman, Launia J. White, Austin M. Veire, Otto Pedraza, Alexander R. Burch, Andrea C. Bozoki, Bradford C. Dickerson, Kimiko Domoto-Reilly, Tatiana Foroud, Leah K. Forsberg, Douglas R. Galasko, Nupur Ghoshal, Neill R. Graff-Radford, Murray Grossman, Hilary W. Heuer, Edward D. Huey, Ging-Yuek R. Hsiung, David J. Irwin, Daniel Kaufer, Gabriel C. Leger, Irene Litvan, Joseph C. Masdeu, Mario F. Mendez, Chiadi U. Onyike, Belen Pascual, Aaron Ritter, Erik D. Roberson, Julio C. Rojas, Maria Carmela Tartaglia, Zbigniew K. Wszolek, Howard Rosen, Bradley F. Boeve, Adam L. Boxer, Leonard Petrucelli
Summary: Blood neurofilament light (NfL) shows promise as a biomarker for frontotemporal dementia (FTD), aiding in early diagnosis, participant selection for prevention or early treatment trials, and improving patient care and treatment outcome estimations.
CELL REPORTS MEDICINE
(2022)
Correction
Medicine, Research & Experimental
Lauren Herl Martens, Jiasheng Zhang, Sami J. Barmada, Ping Zhou, Sherry Kamiya, Binggui Sun, Sang-Won Min, Li Gan, Steven Finkbeiner, Eric J. Huang, Robert V. Farese
JOURNAL OF CLINICAL INVESTIGATION
(2022)