Reduced immunoreactivity to calcium-binding proteins in Purkinje cells precedes onset of ataxia in spinocerebellar ataxia-1 transgenic mice

Neurology. 1998 Jan;50(1):106-13. doi: 10.1212/wnl.50.1.106.

Abstract

Earlier we have shown alterations in immunoreactivity (IR) to the calcium-binding proteins parvalbumin (PV) and calbindin D-28k (CaB) in surviving Purkinje cells of patients with spinocerebellar ataxia-1 (SCA-1). In the present study we determined PV and CaB expression (by immunohistochemical and immunoblot analyses) in Purkinje cells of transgenic mice (TM) expressing the human SCA-1 gene with an expanded (line B05) and normal (line A02) CAG tract, as well as in age-matched nontransgenic mice (nTM). Heterozygotes in the B05 line develop progressive ataxia beginning around 12 weeks of age. A02 animals are phenotypically indistinguishable from wild-type (nontransgenic) animals. In the cerebella of 8-, 9-, and 12-week-old TM-B05 there was a progressive decrease in PV IR in Purkinje cells compared with nTM and TM-A02. Parvalbumin immunostaining in interneurons was well preserved in all groups. A progressive decrease was also observed in CaB IR in Purkinje cells of 8-, 9-, and 12-week-old TM-B05. Cerebellar Purkinje cells of 6-week-old TM-B05, which exhibit no ataxia and even lack demonstrable Purkinje cell loss, also revealed reduction in PV IR. This change was matched by a significant decrease in the amount of cerebellar PV in 6-week-old TM-B05 as determined by Western blot analysis. Calbindin D-28K immunohistochemistry did not detect any marked changes in CaB IR within Purkinje cells at 4 weeks. However, at 6 weeks immunostaining and immunoblot analysis revealed a significant decrease in CaB in TM-B05 compared with controls. These data suggest that decreased levels of calcium-binding proteins in Purkinje cells in SCA-1 transgenic mice may cause alteration in Ca2+ homeostasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Antibodies, Monoclonal
  • Calbindins
  • Calcium-Binding Proteins / genetics*
  • Calcium-Binding Proteins / immunology*
  • Calcium-Binding Proteins / metabolism
  • Cerebellum / chemistry
  • Cerebellum / metabolism
  • DNA, Complementary
  • Disease Models, Animal
  • Gene Expression
  • Mice
  • Mice, Transgenic
  • Nerve Degeneration / metabolism
  • Nitric Oxide Synthase / analysis
  • Parvalbumins / analysis
  • Parvalbumins / immunology
  • Parvalbumins / metabolism
  • Purkinje Cells / chemistry*
  • Purkinje Cells / enzymology
  • S100 Calcium Binding Protein G / analysis
  • S100 Calcium Binding Protein G / immunology
  • Spinocerebellar Degenerations / metabolism*
  • Spinocerebellar Degenerations / physiopathology
  • Transgenes

Substances

  • Antibodies, Monoclonal
  • Calbindins
  • Calcium-Binding Proteins
  • DNA, Complementary
  • Parvalbumins
  • S100 Calcium Binding Protein G
  • Nitric Oxide Synthase