Genetic Modeling of the Neurodegenerative Disease Spinocerebellar Ataxia Type 1 in Zebrafish

Int J Mol Sci. 2021 Jul 8;22(14):7351. doi: 10.3390/ijms22147351.

Abstract

Dominant spinocerebellar ataxias (SCAs) are progredient neurodegenerative diseases commonly affecting the survival of Purkinje cells (PCs) in the human cerebellum. Spinocerebellar ataxia type 1 (SCA1) is caused by the mutated ataxin1 (Atx1) gene product, in which a polyglutamine stretch encoded by CAG repeats is extended in affected SCA1 patients. As a monogenetic disease with the Atx1-polyQ protein exerting a gain of function, SCA1 can be genetically modelled in animals by cell type-specific overexpression. We have established a transgenic PC-specific SCA1 model in zebrafish coexpressing the fluorescent reporter protein mScarlet together with either human wild type Atx1[30Q] as control or SCA1 patient-derived Atx1[82Q]. SCA1 zebrafish display an age-dependent PC degeneration starting at larval stages around six weeks postfertilization, which continuously progresses during further juvenile and young adult stages. Interestingly, PC degeneration is observed more severely in rostral than in caudal regions of the PC population. Although such a neuropathology resulted in no gross locomotor control deficits, SCA1-fish with advanced PC loss display a reduced exploratory behaviour. In vivo imaging in this SCA1 model may help to better understand such patterned PC death known from PC neurodegeneration diseases, to elucidate disease mechanisms and to provide access to neuroprotective compound characterization in vivo.

Keywords: Purkinje cells; bioimaging; cerebellum; neurodegeneration; polyglutamine disease; spinocerebellar ataxia type 1; zebrafish.

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Ataxin-1 / genetics*
  • Ataxin-1 / physiology
  • Cell Death
  • Disease Models, Animal*
  • Disease Progression
  • Exploratory Behavior
  • Genes, Reporter
  • Humans
  • Larva
  • Luminescent Proteins / genetics
  • Purkinje Cells / pathology
  • Spinocerebellar Ataxias / genetics*
  • Transgenes
  • Trinucleotide Repeat Expansion
  • Zebrafish / genetics*
  • Zebrafish / growth & development
  • Zebrafish Proteins / genetics*
  • Zebrafish Proteins / physiology

Substances

  • ATXN1 protein, human
  • Ataxin-1
  • Luminescent Proteins
  • Zebrafish Proteins
  • red fluorescent protein