Expansion of the polyQ repeat in ataxin-2 alters its Golgi localization, disrupts the Golgi complex and causes cell death

Hum Mol Genet. 2003 Jul 1;12(13):1485-96. doi: 10.1093/hmg/ddg175.


Spinocerebellar ataxia type 2 (SCA2) is caused by the expansion of a polyglutamine (polyQ) repeat in ataxin-2, the SCA2 gene product. In contrast to other polyQ diseases, intranuclear inclusions are not prominent in SCA2. In animal models with expression of mutant ataxin-2 targeted to Purkinje cells, neuronal dysfunction and morphologic changes are observed without the formation of intranuclear aggregates. In this report, we investigated the mechanisms underlying SCA2 pathogenesis using cellular models. We confirmed that the SCA2 gene product, ataxin-2, was predominantly located in the Golgi apparatus. Deletion of ER-exit and trans-Golgi signals in ataxin-2 resulted in an altered subcellular distribution. Expression of full-length ataxin-2 with an expanded repeat disrupted the normal morphology of the Golgi complex and colocalization with Golgi markers was lost. Intranuclear inclusions were only seen when the polyQ repeat was expanded to 104 glutamines, and even then were only observed in a small minority of cells. Expression of ataxin-2 with expanded repeats in PC12 and COS1 cells increased cell death compared with normal ataxin-2 and elevated the levels of activated caspase-3 and TUNEL-positive cells. These results suggest a link between cell death mediated by mutant ataxin-2 and the stability of the Golgi complex. The formation of intranuclear aggregates is not necessary for in vitro cell death caused by expression of full-length mutant ataxin-2.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis
  • Ataxins
  • Blotting, Western
  • Brefeldin A / pharmacology
  • COS Cells
  • Caspase 3
  • Caspases / metabolism
  • Cell Death
  • Cell Division
  • Golgi Apparatus / metabolism
  • Golgi Apparatus / pathology*
  • Green Fluorescent Proteins
  • Humans
  • Immunohistochemistry
  • In Situ Nick-End Labeling
  • Luminescent Proteins / metabolism
  • Mice
  • Microscopy, Confocal
  • Microscopy, Fluorescence
  • Mutation
  • Nerve Tissue Proteins
  • Neurons / metabolism
  • PC12 Cells
  • Peptides / chemistry
  • Peptides / genetics*
  • Plasmids / metabolism
  • Protein Synthesis Inhibitors / pharmacology
  • Proteins / genetics*
  • Rats
  • Recombinant Fusion Proteins / metabolism
  • Subcellular Fractions / metabolism
  • Time Factors
  • Transfection


  • Ataxins
  • Luminescent Proteins
  • Nerve Tissue Proteins
  • Peptides
  • Protein Synthesis Inhibitors
  • Proteins
  • Recombinant Fusion Proteins
  • Green Fluorescent Proteins
  • Brefeldin A
  • polyglutamine
  • CASP3 protein, human
  • Casp3 protein, mouse
  • Casp3 protein, rat
  • Caspase 3
  • Caspases