Identification of genes that modify ataxin-1-induced neurodegeneration

Nature. 2000 Nov 2;408(6808):101-6. doi: 10.1038/35040584.


A growing number of human neurodegenerative diseases result from the expansion of a glutamine repeat in the protein that causes the disease. Spinocerebellar ataxia type 1 (SCA1) is one such disease-caused by expansion of a polyglutamine tract in the protein ataxin-1. To elucidate the genetic pathways and molecular mechanisms underlying neuronal degeneration in this group of diseases, we have created a model system for SCA1 by expressing the full-length human SCA1 gene in Drosophila. Here we show that high levels of wild-type ataxin-1 can cause degenerative phenotypes similar to those caused by the expanded protein. We conducted genetic screens to identify genes that modify SCA1-induced neurodegeneration. Several modifiers highlight the role of protein folding and protein clearance in the development of SCA1. Furthermore, new mechanisms of polyglutamine pathogenesis were revealed by the discovery of modifiers that are involved in RNA processing, transcriptional regulation and cellular detoxification. These findings may be relevant to the treatment of polyglutamine diseases and, perhaps, to other neurodegenerative diseases, such as Alzheimer's and Parkinson's disease.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Ataxin-1
  • Ataxins
  • Disease Models, Animal
  • Drosophila
  • Female
  • Heat-Shock Response / genetics
  • Humans
  • Inclusion Bodies
  • Male
  • Nerve Degeneration / genetics*
  • Nerve Tissue Proteins / genetics*
  • Neurodegenerative Diseases / genetics*
  • Neurodegenerative Diseases / pathology
  • Nuclear Proteins / genetics*
  • Phenotype
  • Protein Folding
  • Retina / metabolism
  • Spinocerebellar Ataxias / genetics*
  • Spinocerebellar Ataxias / pathology


  • ATXN1 protein, human
  • Ataxin-1
  • Ataxins
  • Nerve Tissue Proteins
  • Nuclear Proteins