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

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

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

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.

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GERLS Fellowhsip Egypt Ministry of Higher Education and Scientific Research and Deutscher Akademischer Austauschdienst

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

0 (ATXN1 protein, human)
0 (Ataxin-1)
0 (Luminescent Proteins)
0 (Zebrafish Proteins)

Date Created: 20210724 Date Completed: 20210817 Latest Revision: 20231213

20231215

PMC8306488

10.3390/ijms22147351

34298970