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 Detalle_Publicacion

Blood transcriptome sequencing identifies biomarkers able to track disease stages in spinocerebellar ataxia type 3

Abstract: Transcriptional dysregulation has been described in spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD), an autosomal dominant ataxia caused by a polyglutamine expansion in the ataxin-3 protein. As ataxin-3 is ubiquitously expressed, transcriptional alterations in blood may reflect early changes that start before clinical onset and might serve as peripheral biomarkers in clinical and research settings. Our goal was to describe enriched pathways and report dysregulated genes, which can track disease onset, severity or progression in carriers of the ATXN3 mutation (pre-ataxic subjects and patients). Global dysregulation patterns were identified by RNA sequencing of blood samples from 40 carriers of ATXN3 mutation and 20 controls and further compared with transcriptomic data from post-mortem cerebellum samples of MJD patients and controls. Ten genes?ABCA1, CEP72, PTGDS, SAFB2, SFSWAP, CCDC88C, SH2B1, LTBP4, MEG3 and TSPOAP1?whose expression in blood was altered in the pre-ataxic stage and simultaneously, correlated with ataxia severity in the overt disease stage, were analysed by quantitative real-time PCR in blood samples from an independent set of 170 SCA3/MJD subjects and 57 controls. Pathway enrichment analysis indicated the G?i signalling and the oestrogen receptor signalling to be similarly affected in blood and cerebellum. SAFB2, SFSWAP and LTBP4 were consistently dysregulated in pre-ataxic subjects compared to controls, displaying a combined discriminatory ability of 79%. In patients, ataxia severity was associated with higher levels of MEG3 and TSPOAP1. We propose expression levels of SAFB2, SFSWAP and LTBP4 as well as MEG3 and TSPOAP1 as stratification markers of SCA3/MJD progression, deserving further validation in longitudinal studies and in independent cohorts.

 Autoría: Raposo M., Hübener-Schmid J., Ferreira A.F., Vieira Melo A.R., Vasconcelos J., Pires P., Kay T., Garcia-Moreno H., Giunti P., Santana M.M., De Almeida L.P., Infante J., Van De Warrenburg B.P., De Vries J.J., Faber J., Klockgether T., Casadei N., Admard J., Schöls L., Riess O., Lima M., Krahe J., Reetz K., González J., Gonzalez C., Baptista C., Lemos J., Giordano I., Grobe-Einsler M., Önder D., Silva P., Januário C., Ribeiro J., Cu

 Fuente: Brain, 2023, 146(10), 4132-4143

Editorial: Oxford University Press

 Fecha de publicación: 03/10/2023

Nº de páginas: 12

Tipo de publicación: Artículo de Revista

 DOI: 10.1093/brain/awad128

ISSN: 0006-8950,1460-2156

Url de la publicación: https://doi.org/10.1093/brain/awad128

Autoría

RAPOSO, MAFALDA

HÜBENER-SCHMID, JEANNETTE

FERREIRA, ANA F.

VIEIRA MELO, ANA ROSA

VASCONCELOS, JOAO

PIRES, PAULA

KAY, TERESA

GARCÍA-MORENO, HÉCTOR

GIUNTI, PAOLA

SANTANA, MAGDA M.

PEREIRA DE ALMEIDA, LUIS

WARRENBURG, BART P. VAN DE

VRIS, JEROEN J. DE

FABER, JENNIFER

KLOCKGETHER, THOMAS

CASADEI, NICOLAS

ARMAND, JAKOB

SCHÖLS, LUDGER