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C9orf72-associated dipeptide protein repeats form A11-positive oligomers in amyotrophic lateral sclerosis and frontotemporal dementia.
Bhatt, Nemil; Puangmalai, Nicha; Sengupta, Urmi; Jerez, Cynthia; Kidd, Madison; Gandhi, Shailee; Kayed, Rakez.
Afiliación
  • Bhatt N; Mitchell Center for Neurodegenerative Disease, University of Texas Medical Branch, Galveston, Texas, USA; Department of Neurology, Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas, USA.
  • Puangmalai N; Mitchell Center for Neurodegenerative Disease, University of Texas Medical Branch, Galveston, Texas, USA; Department of Neurology, Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas, USA.
  • Sengupta U; Mitchell Center for Neurodegenerative Disease, University of Texas Medical Branch, Galveston, Texas, USA; Department of Neurology, Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas, USA.
  • Jerez C; Mitchell Center for Neurodegenerative Disease, University of Texas Medical Branch, Galveston, Texas, USA; Department of Neurology, Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas, USA.
  • Kidd M; Mitchell Center for Neurodegenerative Disease, University of Texas Medical Branch, Galveston, Texas, USA; Department of Neurology, Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas, USA.
  • Gandhi S; Mitchell Center for Neurodegenerative Disease, University of Texas Medical Branch, Galveston, Texas, USA; Department of Neurology, Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas, USA.
  • Kayed R; Mitchell Center for Neurodegenerative Disease, University of Texas Medical Branch, Galveston, Texas, USA; Department of Neurology, Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas, USA. Electronic address: rakayed@utmb.edu.
J Biol Chem ; 300(2): 105628, 2024 Feb.
Article en En | MEDLINE | ID: mdl-38295729
ABSTRACT
Hexanucleotide repeat expansion in C9orf72 is one of the most common causes of amyotrophic lateral sclerosis and frontotemporal dementia. The hexanucleotide expansion, formed by GGGGCC (G4C2) repeats, leads to the production of five dipeptide protein repeats (DPRs) via repeat-associated non-AUG translation. Among the five dipeptide repeats, Gly-Arg, Pro-Arg, and Gly-Ala form neuronal inclusions that contain aggregates of the peptides. Several studies have attempted to model DPR-associated toxicity using various repeat lengths, which suggests a unique conformation that is cytotoxic and is independent of the repeat length. However, the structural characteristics of DPR aggregates have yet to be determined. Increasing evidence suggests that soluble species, such as oligomers, are the main cause of toxicity in proteinopathies, such as Alzheimer's and Parkinson's disease. To investigate the ability of DPRs to aggregate and form toxic oligomers, we adopted a reductionist approach using small dipeptide repeats of 3, 6, and 12. This study shows that DPRs, particularly glycine-arginine and proline-arginine, form oligomers that exhibit distinct dye-binding properties and morphologies. Importantly, we also identified toxic DPR oligomers in amyotrophic lateral sclerosis and frontotemporal dementia postmortem brains that are morphologically similar to those generated recombinantly. This study demonstrates that, similar to soluble oligomers formed by various amyloid proteins, DPR oligomers are toxic, independent of their repeat length.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Demencia Frontotemporal / Esclerosis Amiotrófica Lateral Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: J Biol Chem Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Demencia Frontotemporal / Esclerosis Amiotrófica Lateral Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: J Biol Chem Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos