Regional rescue of spinocerebellar ataxia type 1 phenotypes by 14-3-3ε haploinsufficiency in mice underscores complex pathogenicity in neurodegeneration

Paymaan Jafar-Nejad, Christopher S. Ward, Ronald Richman, Harry T. Orr, Huda Y. Zoghbi

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease caused by the expansion of a CAG repeat encoding a polyglutamine tract in Ataxin-1 (ATXN1). Both WT and mutant ATXN1 interact with 14-3-3 proteins, and 14-3-3 overexpression stabilizes ATXN1 levels in cells and increases ATXN1 toxicity in flies. To determine whether reducing 14-3-3 levels might mitigate SCA1 pathogenesis, we bred Sca1154Q/+ mice to mice lacking one allele of 14-3-3ε. 14-3-3ε haploinsufficiency rescued cerebellar pathology and motor phenotypes but, surprisingly, not weight loss, respiratory dysfunction, or premature lethality. Biochemical studies revealed that reducing 14-3-3ε levels exerted different effects intwo brain regions especially vulnerable in SCA1: Although diminishing levels of both WT and mutant ATXN1 in the cerebellum, 14-3-3ε haploinsufficiency did not alter ATXN1 levels in the brainstem. Furthermore, 14-3-3ε haploinsufficiency decreased the incorporation of expanded ATXN1 into its large toxic complexes in the cerebellum but not in the brainstem, and the distribution of ATXN1's small and large native complexes differed significantly between the two regions. These data suggest that distinct pathogenic mechanisms operate in different vulnerable brain regions, adding another level of complexity to SCA1 pathogenesis.

Original languageEnglish (US)
Pages (from-to)2142-2147
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number5
DOIs
StatePublished - Feb 1 2011

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Spinocerebellar Ataxias
Haploinsufficiency
Virulence
Phenotype
14-3-3 Proteins
Cerebellum
Brain Stem
Poisons
Brain
Ataxin-1
Diptera
Neurodegenerative Diseases
Weight Loss
Alleles
Pathology

Keywords

  • Ataxin1-like
  • Capicua
  • Purkinje
  • RBM17
  • Ywhae

Cite this

Regional rescue of spinocerebellar ataxia type 1 phenotypes by 14-3-3ε haploinsufficiency in mice underscores complex pathogenicity in neurodegeneration. / Jafar-Nejad, Paymaan; Ward, Christopher S.; Richman, Ronald; Orr, Harry T.; Zoghbi, Huda Y.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 108, No. 5, 01.02.2011, p. 2142-2147.

Research output: Contribution to journalArticle

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