Wyniki wyszukiwania

Sortuj według:

Ogranicz wyniki do:

First humanized ataxin-3 knock-in mouse model presents molecular and histopathological phenotypes of spinocerebellar ataxia type 3

100%

Switonski P. M., Krzyzosiak W. J., Figiel M.

Acta Neurobiologiae Experimentalis

2013

tom 73

nr Suppl.1

Spinocerebellar ataxia type 3 (SCA3) is a human neurodegenerative disorder caused by the expansion of CAG repeats in the coding region of the ataxin-3 gene. We generated the first humanized SCA3 knock-in mouse model by introducing human cDNA for ataxin-3 with 91 CAG repeats into the mouse ataxin-3 locus. The resulting animals express human mutant ataxin-3 protein in multiple brain structures and non-neuronal tissues. Like in human patients, the humanized allele shows both somatic and intergenerational CAG instability. The intergenerational instability is significantly associated with the gender of parent. Offspring inherits expanded CAG repeats in paternal transmissions and contracted CAG repeats in maternal transmissions. Moreover, mice show early upregulation of Serpina3n gene expression in the brain as early as at 7 weeks of age. This upregulation is also present in astrocytes isolated from neonatal animals, which suggest that mutant ataxin-3 has a more direct influence on a Serpina3n expression. The knock-in animals also demonstrate histopathological hallmarks of SCA3, including the damage of Purkinje cells in the cerebellum and the presence of intranuclear ataxin-3 inclusions.

YAC128 mouse model-derived iPSCs show markers of Huntington disease

100%

Szlachcic W. J., Switonski P. M., Krzyzosiak W. J., Figiel M.

Acta Neurobiologiae Experimentalis

2013

tom 73

nr Suppl.1

Huntington disease (HD) is an incurable brain disorder caused by expansion of CAG repeats in a HTT gene resulting in toxic huntingtin with long polyglutamine tract. In HD, neurons die in cerebral cortex and striatum and therefore a treatment option is a cell therapy using cells generated from induced pluripotent stem cells (iPSC) from patients. We have established a model of such therapy comprising iPSCs lines from the adult dermal fibroblasts of YAC128 HD mouse model. The cells were reprogrammed using transposable and excisable piggyBac vector expressing OSKML transcription factors. These iPSC cells show pluripotency both in in vitro (Tuj-positive neurons and beating cardiomiocytes) and in vivo (teratoma formation) differentiation assays, thus being suitable for experimental cell therapy. In addition, our YAC128/iPSC show alterations of Wnt/β-catenin and MAPK signaling pathways probably resulting from expression of human mutant huntingtin. Thus, cells suitable for cell therapy would need silencing of the mutant huntingtin. Therefore we have generated a series of therapeutic constructs based on piggyBac transposon expressing anti-huntingtin siRNAs in sh-miR backbone. We show that the construct when integrated into iPSC genome efficiently silences mutant huntingtin expression. Our platform is a useful model for investigating cell therapy outcomes in the HD mouse model.

Ograniczanie wyników

2 Acta Neurobiologiae Experimentalis

2 Figiel M.

2 Krzyzosiak W. J.

2 Switonski P. M.

1 Szlachcic W. J.

2 2013

Wyniki wyszukiwania

First humanized ataxin-3 knock-in mouse model presents molecular and histopathological phenotypes of spinocerebellar ataxia type 3

YAC128 mouse model-derived iPSCs show markers of Huntington disease