Phenotypic effects of expanded ataxin-1 polyglutamines with interruptions in vitro

Valentina Calabresi, Serena Guida, Antonio Servadio, Carla Jodice

Research output: Contribution to journalArticle

Abstract

Spinocerebellar ataxia type 1 is a neurodegenerative disease caused by expansion of an uninterrupted glutamine repeat in ataxin-1 protein. Protein aggregation and immunoreactivity to 1C2 monoclonal antibody are two distinct pathognomonic features of expanded ataxin-1, as well as of other polyglutamine disorders. Rare cases of non-affected elderly subjects carrying expanded ataxin-1 alleles were found in random population. However, in these alleles the glutamine stretch was interrupted by histidines. Due to lack of phenotype, these alleles should be considered 'normal'. Most importantly, occurrence of these unusual alleles provides a unique opportunity to investigate which molecular properties of expanded ataxin-1 are not coupled to polyglutamine pathogenesis. Towards this goal, we compared in vitro the immunoreactivity to 1C2 antibody and the ability to form aggregates of interrupted and uninterrupted alleles. Immunoblotting showed that expanded-interrupted ataxin-1 had an affinity to 1C2 resembling that of normal ataxin-1. On the contrary, filter assay showed that aggregation rate of expanded-interrupted ataxin-1 resembles that of expanded-uninterrupted ataxin-1. These observations indicate that affinity for 1C2 does not directly correlate with self-aggregation of ataxin-1. Moreover, self-aggregation is not directly affected by histidine interruptions. In conclusion, these results support the hypothesis that mechanisms underlying neuronal degeneration are triggered by protein misfolding rather than by protein aggregation.

Original languageEnglish
Pages (from-to)337-342
Number of pages6
JournalBrain Research Bulletin
Volume56
Issue number3-4
DOIs
Publication statusPublished - Nov 1 2001

Fingerprint

Alleles
Glutamine
Histidine
Spinocerebellar Ataxias
In Vitro Techniques
polyglutamine
Ataxin-1
Proteins
Immunoblotting
Neurodegenerative Diseases
Monoclonal Antibodies
Phenotype
Antibodies
Population

Keywords

  • Amyloid-like protein aggregates
  • SCA1
  • Spinocerebellar ataxia type 1
  • Trinucleotide expansion

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Phenotypic effects of expanded ataxin-1 polyglutamines with interruptions in vitro. / Calabresi, Valentina; Guida, Serena; Servadio, Antonio; Jodice, Carla.

In: Brain Research Bulletin, Vol. 56, No. 3-4, 01.11.2001, p. 337-342.

Research output: Contribution to journalArticle

Calabresi, Valentina ; Guida, Serena ; Servadio, Antonio ; Jodice, Carla. / Phenotypic effects of expanded ataxin-1 polyglutamines with interruptions in vitro. In: Brain Research Bulletin. 2001 ; Vol. 56, No. 3-4. pp. 337-342.
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