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

被引:7
作者
Calabresi, V
Guida, S
Servadio, A
Jodice, C
机构
[1] Univ Roma Tor Vergata, Dept Biol, I-00133 Rome, Italy
[2] San Raffaele Sci Inst, Inst Stem Cell Res, I-20132 Milan, Italy
关键词
spinocerebellar ataxia type 1; SCA1; trinucleotide expansion; amyloid-like protein aggregates;
D O I
10.1016/S0361-9230(01)00600-1
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Spinocerebellar ataxia type I 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 ather than by protein aggregation. (C) 2001 Elsevier Science Inc.
引用
收藏
页码:337 / 342
页数:6
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