Blood and cerebellar abundance of ATXN3 splice variants in spinocerebellar ataxia type 3/Machado-Joseph disease.

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Autores de IDIVAL

  • Jon Infante Ceberio

    Autor

Autores ajenos al IDIVAL

  • Raposo M
  • Hübener-Schmid J
  • Tagett R
  • Ferreira AF
  • Melo ARV
  • Vasconcelos J
  • Pires P
  • Kay T
  • Garcia-Moreno H
  • Giunti P
  • Santana MM
  • de Almeida LP
  • van de Warrenburg BP
  • de Vries JJ
  • Faber J
  • Klockgether T
  • Casadei N
  • Admard J
  • Schöls L
  • Riess O
  • European Spinocerebellar ataxia type 3/Machado-Joseph disease Initiative (ESMI)
  • do Carmo Costa M
  • Lima M

Unidades

Abstract

Spinocerebellar ataxia type 3 (SCA3)/Machado-Joseph disease (MJD) is a heritable proteinopathy disorder, whose causative gene, ATXN3, undergoes alternative splicing. Ataxin-3 protein isoforms differ in their toxicity, suggesting that certain ATXN3 splice variants may be crucial in driving the selective toxicity in SCA3. Using RNA-seq datasets we identified and determined the abundance of annotated ATXN3 transcripts in blood (n?=?60) and cerebellum (n?=?12) of SCA3 subjects and controls. The reference transcript (ATXN3-251), translating into an ataxin-3 isoform harbouring three ubiquitin-interacting motifs (UIMs), showed the highest abundance in blood, while the most abundant transcript in the cerebellum (ATXN3-208) was of unclear function. Noteworthy, two of the four transcripts that encode full-length ataxin-3 isoforms but differ in the C-terminus were strongly related with tissue expression specificity: ATXN3-251 (3UIM) was expressed in blood 50-fold more than in the cerebellum, whereas ATXN3-214 (2UIM) was expressed in the cerebellum 20-fold more than in the blood. These findings shed light on ATXN3 alternative splicing, aiding in the comprehension of SCA3 pathogenesis and providing guidance in the design of future ATXN3 mRNA-lowering therapies.

Copyright © 2024. Published by Elsevier Inc.

Datos de la publicación

ISSN/ISSNe:
0969-9961, 1095-953X

NEUROBIOLOGY OF DISEASE  ACADEMIC PRESS INC ELSEVIER SCIENCE

Tipo:
Article
Páginas:
106456-106456
PubMed:
38423193
Enlace a otro recurso:
www.sciencedirect.com

Citas Recibidas en Web of Science: 1

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Keywords

  • Alternative splicing; Ataxin-3; Neurodegenerative disease; RNA-seq; mRNA; polyQ diseases

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