Hexanucleotide Repeat Expansions in c9FTD/ALS and SCA36 Confer Selective Patterns of Neurodegeneration In Vivo
Todd, T. W.; McEachin, Z. T.; Chew, J.; Burch, A. R.; Jansen-West, K.; Tong, J. M.; Yue, M.; Song, Y. P.; Castanedes-Casey, M.; Kurti, A.; Dunmore, J. H.; Fryer, J. D.; Zhang, Y. J.; San Millan Tejado, Beatriz; Teijeira Bautista, Susana; Arias Gómez, Manuel; Dickson, D.; Gendron, T. F.; Sobrido Gómez, María Jesús; Disney, M. D.; Bassell, G. J.; Rossoll, W.; Petrucelli, L.
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Identificadores
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Fecha de publicación
2020Título de revista
Cell Reports
Tipo de contenido
Journal Article
DeCS
ARN | proteínas nucleares | neuronas | expansión de las repeticiones de ADN | animales | humanos | esclerosis lateral amiotrófica | cuerpos de inclusión | demencia frontotemporal | ratonesMeSH
Humans | RNA | Neurons | Amyotrophic Lateral Sclerosis | Mice | Inclusion Bodies | DNA Repeat Expansion | Animals | Frontotemporal Dementia | Nuclear ProteinsResumen
A G4C2 hexanucleotide repeat expansion in an intron of C9orf72 is the most common cause of frontal temporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS). A remarkably similar intronic TG3C2 repeat expansion is associated with spinocerebellar ataxia 36 (SCA36). Both expansions are widely expressed, form RNA foci, and can undergo repeat-associated non-ATG (RAN) translation to form similar dipeptide repeat proteins (DPRs). Yet, these diseases result in the degeneration of distinct subsets of neurons. We show that the expression of these repeat expansions in mice is sufficient to recapitulate the unique features of each disease, including this selective neuronal vulnerability. Furthermore, only the G4C2 repeat induces the formation of aberrant stress granules and pTDP-43 inclusions. Overall, our results demonstrate that the pathomechanisms responsible for each disease are intrinsic to the individual repeat sequence, highlighting the importance of sequence-specific RNA-mediated toxicity in each disorder.
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