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.
Highlights
Spinocerebellar ataxia type 1 (SCA1) is an adult onset, autosomal dominant neurodegenerative disease, in which Purkinje cells (PCs) of the cerebellum are among the most prominent neuronal populations that are affected by progressive cytotoxicity and cell death [1]
At least for Huntington’s disease, another neurodegenerative polyglutamine disease, it was shown that interruption of the polyQstretch significantly decreases toxicity, and that the length of the non-interrupted polyQstretch rather than its overall length determines the onset of the disease [10]
We have recently demonstrated that a small genomic element upstream of the zebrafish gene carbonic anhydrase 8, named cpce, is able to exclusively drive expression in zebrafish PCs starting at their timepoint of differentiation, which initiates roughly at 2.5 days postfertilization [25]
Summary
Spinocerebellar ataxia type 1 (SCA1) is an adult onset, autosomal dominant neurodegenerative disease, in which Purkinje cells (PCs) of the cerebellum are among the most prominent neuronal populations that are affected by progressive cytotoxicity and cell death [1]. SCA1 is an inherited monogenetic disease largely caused by gain of function of the human Ataxin protein (Atx1) [6] This protein contains a polyglutamine (polyQ) stretch of variable length in its N-terminus, with non-interrupted polyQ-stretches of above 40 glutamine residues leading to SCA1 symptoms and neurodegeneration [7,8]. We have recently developed an approach to genetically target differentiating and mature zebrafish PCs with co-expression of several transgenes [25] We have used this tool to establish a genetic model of human SCA1 in zebrafish for observing affected PCs using fluorescent protein reporters and to monitor the behavioural performance of affected fish in relation to their disease progression
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