A new humanized ataxin-3 knock-in mouse model combines the genetic features, pathogenesis of neurons and glia and late disease onset of SCA3/MJD

Neurobiol Dis. 2015 Jan;73:174-88. doi: 10.1016/j.nbd.2014.09.020. Epub 2014 Oct 7.


Spinocerebellar ataxia type 3 (SCA3/MJD) is a neurodegenerative disease triggered by the expansion of CAG repeats in the ATXN3 gene. Here, we report the generation of the first humanized ataxin-3 knock-in mouse model (Ki91), which provides insights into the neuronal and glial pathology of SCA3/MJD. First, mutant ataxin-3 accumulated in cell nuclei across the Ki91 brain, showing diffused immunostaining and forming intranuclear inclusions. The humanized allele revealed expansion and contraction of CAG repeats in intergenerational transmissions. CAG mutation also exhibited age-dependent tissue-specific expansion, which was most prominent in the cerebellum, pons and testes of Ki91 animals. Moreover, Ki91 mice displayed neuroinflammatory processes, showing astrogliosis in the cerebellar white matter and the substantia nigra that paralleled the transcriptional deregulation of Serpina3n, a molecular sign of neurodegeneration and brain damage. Simultaneously, the cerebellar Purkinje cells in Ki91 mice showed neurodegeneration, a pronounced decrease in Calbindin D-28k immunoreactivity and a mild decrease in cell number, thereby modeling the degeneration of the cerebellum observed in SCA3. Moreover, these molecular and cellular neuropathologies were accompanied by late behavioral deficits in motor coordination observed in rotarod and static rod tests in heterozygous Ki91 animals. In summary, we created an ataxin-3 knock-in mouse model that combines the molecular and behavioral disease phenotypes with the genetic features of SCA3. This model will be very useful for studying the pathogenesis and responses to therapy of SCA3/MJD and other polyQ disorders.

Keywords: Ataxia; Ataxin-3; CAG repeats; Knock-in; Knockin; MJD; Mouse; Polyglutamine; SCA3; Serpina3n; Spinocerebellar.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ataxin-3
  • Brain / pathology*
  • Calbindin 1 / metabolism
  • Disease Models, Animal
  • Encephalitis / etiology
  • Female
  • Gene Expression Regulation / genetics
  • Humans
  • Intranuclear Inclusion Bodies / metabolism
  • Intranuclear Inclusion Bodies / pathology
  • Machado-Joseph Disease / complications
  • Machado-Joseph Disease / genetics*
  • Machado-Joseph Disease / pathology*
  • Male
  • Mice
  • Mice, Transgenic
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Neuroglia / pathology*
  • Neurons / pathology*
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Repressor Proteins / genetics*
  • Repressor Proteins / metabolism
  • Sensation Disorders / etiology
  • Trinucleotide Repeats / genetics


  • Calbindin 1
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Repressor Proteins
  • ATXN3 protein, human
  • Ataxin-3