Article
Multidisciplinary Sciences
Michael R. Das, Yeonji Chang, Rachel Anderson, Nan Zhang, Colson P. Tomberlin, Ronald D. Vale, Ankur Jain
Summary: CAG repeat expansions in neurodegenerative diseases lead to the aggregation of RNA and protein, disrupting nucleocytoplasmic transport and causing cell death. Inhibition of repeat-associated non-AUG (RAN) translation alleviates cell toxicity.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Review
Genetics & Heredity
Manon Boivin, Nicolas Charlet-Berguerand
Summary: Microsatellites are repeated DNA sequences that play important roles in genome regulation and evolution. Expansions of a subset of microsatellites can cause various human genetic diseases. Some of these diseases are characterized by expansions of similar sequences, sizes, and localizations, and they show similar clinical manifestations and histopathological features, suggesting a common disease mechanism.
FRONTIERS IN GENETICS
(2022)
Article
Clinical Neurology
Christel Depienne, Arn M. J. M. van den Maagdenberg, Theresa Kuehnel, Hiroyuki Ishiura, Mark A. Corbett, Shoji Tsuji
Summary: Familial adult myoclonus epilepsy (FAME) is caused by the same TTTTA/TTTCA pentanucleotide repeat expansion in six different genes. The expansion affects proteins with different functions and subcellular locations, leading to neurobiological disturbances and clinical symptoms in FAME subjects. Current hypotheses propose that the expansion's pathophysiological mechanism is independent of the gene and its function, possibly involving toxicity of RNA molecules or polypeptides encoded by the repeats.
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.
Review
Neurosciences
Shaopeng Wang, Shuying Sun
Summary: RNA translation is tightly regulated in eukaryotic cells for gene expression and proteome homeostasis. Dysregulation of translation is involved in neurological diseases including ALS. Recent studies have made advances in understanding how mutant genes and non-canonical translation affect ALS.
MOLECULAR NEURODEGENERATION
(2023)
Article
Biochemistry & Molecular Biology
Helene Tran, Michael P. Moazami, Huiya Yang, Diane McKenna-Yasek, Catherine L. Douthwright, Courtney Pinto, Jake Metterville, Minwook Shin, Nitasha Sanil, Craig Dooley, Ajit Puri, Alexandra Weiss, Nicholas Wightman, Heather Gray-Edwards, Miklos Marosfoi, Robert M. King, Thomas Kenderdine, Daniele Fabris, Robert Bowser, Jonathan K. Watts, Robert H. Brown
Summary: The study successfully generated and optimized ASOs that blunt the G(4)C(2) repeat-containing transcripts in the C9ORF72 gene, demonstrating potential therapeutic efficacy for patients with ALS and FTD.
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)
Article
Biochemistry & Molecular Biology
Shannon E. Wright, Caitlin M. Rodriguez, Jeremy Monroe, Jiazheng Xing, Amy Krans, Brittany N. Flores, Venkatesha Barsur, Magdalena I. Ivanova, Kristin S. Koutmou, Sami J. Barmada, Peter K. Todd
Summary: CGG repeat expansions in the FMR1 gene are associated with the neurodegenerative disease FXTAS. These repeats can form stable RNA secondary structures and undergo aberrant translation in the absence of an AUG start codon, producing aggregate-prone peptides that accumulate in neuronal inclusions and contribute to neurotoxicity. The most abundant RAN translation product, FMRpolyG, is shown to be less toxic when generated from a construct with a non-repetitive alternating codon sequence instead of the CGG repeat. Investigation into the mechanism of this differential toxicity reveals translational frameshifts within the CGG repeat and the formation of chimeric R/G peptides, both of which contribute to CGG repeat-associated toxicity in FXTAS and related disorders.
NUCLEIC ACIDS RESEARCH
(2022)
Review
Biochemistry & Molecular Biology
Joshua L. Schwartz, Krysten Leigh Jones, Gene W. Yeo
Summary: This study discusses the pathological mechanisms and therapeutic potential of various neurological disorders caused by short repeat expansions, including RNA processes, RAN translation, and reducing toxic RNA levels. Promising therapeutic strategies have emerged for these disorders, although treatments are still lacking for most of them.
CRITICAL REVIEWS IN BIOCHEMISTRY AND MOLECULAR BIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Ernest Wang, Ravi Thombre, Yajas Shah, Rachel Latanich, Jiou Wang
Summary: G-quadruplexes (G4s), higher-order DNA and RNA secondary structures with various conformations, play important roles in cellular processes and may have an impact on the pathogenic cascades of neurological diseases. Further research is needed to fully understand their functions and potential implications in disease development.
NUCLEIC ACIDS RESEARCH
(2021)
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)
Article
Biology
Sonia Coni, Federica A. Falconio, Marta Marzullo, Marzia Munafo, Benedetta Zuliani, Federica Mosti, Alessandro Fatica, Zaira Ianniello, Rosa Bordone, Alberto Macone, Enzo Agostinelli, Alessia Perna, Tanja Matkovic, Stephan Sigrist, Gabriella Silvestri, Gianluca Canettieri, Laura Ciapponi
Summary: Expansion of CCTG repeats in the CNBP gene leads to DM2 and is associated with impaired polyamine metabolism. Depletion of CNBP in Drosophila muscles causes aging-dependent locomotor defects correlated with impaired polyamine metabolism. This function of CNBP is evolutionarily conserved in vertebrates and has relevance for CNBP-related pathophysiological conditions.
Article
Multidisciplinary Sciences
Katharina E. Meijboom, Abbas Abdallah, Nicholas P. Fordham, Hiroko Nagase, Tomas Rodriguez, Carolyn Kraus, Tania F. Gendron, Gopinath Krishnan, Rustam Esanov, Nadja S. Andrade, Matthew J. Rybin, Melina Ramic, Zachary D. Stephens, Alireza Edraki, Meghan T. Blackwood, Aydan Kahriman, Nils Henninger, Jean-Pierre A. Kocher, Michael Benatar, Michael H. Brodsky, Leonard Petrucelli, Fen-Biao Gao, Erik J. Sontheimer, Robert H. Brown, Zane Zeier, Christian Mueller
Summary: A hexanucleotide repeat expansion in C9ORF72 is the most common genetic cause of ALS and FTD. Here, the authors demonstrate CRISPR/Cas9 excision of the expansion results in a rescue of disease mechanisms in vivo and in vitro.
NATURE COMMUNICATIONS
(2022)
Review
Biochemistry & Molecular Biology
Ye Teng, Ming Zhu, Zhidong Qiu
Summary: Repeat expansions are the main genetic cause of various neurodegeneration diseases. G-rich repeat sequences, such as CGG and GGGGCC, form functional G-quadruplexes and play important roles in bioprocesses. This review provides an overview of the contribution of G-quadruplex in repeat expansion disorders and summarizes the related mechanisms, including genetic instabilities, toxic RNA foci, and protein/peptide dysfunction.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Biochemistry & Molecular Biology
Yuzo Fujino, Kohji Mori, Yoshitaka Nagai
Summary: Expanded short tandem repeats cause more than 50 monogenic diseases, which are mostly neuromuscular diseases. Recently, it has been discovered that expanded repeat sequences can be translated into repeat polypeptides through non-canonical repeat-associated non-AUG translation (RAN translation). These translated repeat polypeptides have been proven to be toxic and play a role in the pathogenesis of repeat expansion diseases.
JOURNAL OF BIOCHEMISTRY
(2023)
