A novel transgenic rat model for spinocerebellar ataxia type 17 recapitulates neuropathological changes and supplies in vivo imaging biomarkers

J Neurosci. 2013 May 22;33(21):9068-81. doi: 10.1523/JNEUROSCI.5622-12.2013.

Abstract

Spinocerebellar ataxia 17 (SCA17) is an autosomal-dominant, late-onset neurodegenerative disorder caused by an expanded polyglutamine (polyQ) repeat in the TATA-box-binding protein (TBP). To further investigate this devastating disease, we sought to create a first transgenic rat model for SCA17 that carries a full human cDNA fragment of the TBP gene with 64 CAA/CAG repeats (TBPQ64). In line with previous observations in mouse models for SCA17, TBPQ64 rats show a severe neurological phenotype including ataxia, impairment of postural reflexes, and hyperactivity in early stages followed by reduced activity, loss of body weight, and early death. Neuropathologically, the severe phenotype of SCA17 rats was associated with neuronal loss, particularly in the cerebellum. Degeneration of Purkinje, basket, and stellate cells, changes in the morphology of the dendrites, nuclear TBP-positive immunoreactivity, and axonal torpedos were readily found by light and electron microscopy. While some of these changes are well recapitulated in existing mouse models for SCA17, we provide evidence that some crucial characteristics of SCA17 are better mirrored in TBPQ64 rats. Thus, this SCA17 model represents a valuable tool to pursue experimentation and therapeutic approaches that may be difficult or impossible to perform with SCA17 transgenic mice. We show for the first time positron emission tomography (PET) and diffusion tensor imaging (DTI) data of a SCA animal model that replicate recent PET studies in human SCA17 patients. Our results also confirm that DTI are potentially useful correlates of neuropathological changes in TBPQ64 rats and raise hope that DTI imaging could provide a biomarker for SCA17 patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anxiety / etiology
  • Anxiety / genetics
  • Body Weight / genetics
  • Brain / metabolism
  • Brain / pathology
  • Brain / ultrastructure
  • Diffusion Tensor Imaging*
  • Disease Models, Animal*
  • Electronic Data Processing
  • Female
  • Genotype
  • Humans
  • Male
  • Maze Learning
  • Motor Activity
  • Neurologic Examination
  • Positron-Emission Tomography
  • Psychomotor Performance / physiology
  • Raclopride / pharmacokinetics
  • Rats
  • Rats, Transgenic
  • Rotarod Performance Test
  • Severity of Illness Index
  • Spinocerebellar Ataxias* / diagnosis
  • Spinocerebellar Ataxias* / genetics
  • Spinocerebellar Ataxias* / physiopathology
  • TATA-Box Binding Protein / genetics*
  • Trinucleotide Repeat Expansion / genetics*
  • Tubulin / metabolism

Substances

  • TATA-Box Binding Protein
  • Tubulin
  • Raclopride

Supplementary concepts

  • Spinocerebellar Ataxia 17