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Gain and loss of function mutations of ataxin-7 cause cilia pathology in mouse and zebrafish models
© Karam et al. 2015
Published: 13 July 2015
Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant neurodegenerative disease characterized by progressive neuronal loss in the cerebellum and associated structures, leading to cerebellar ataxia, dysarthria and dysphagia. Additional non-cerebellar symptoms are present at variable frequencies, including visual impairment affecting 83% of patients that is caused by cone and rod photoreceptor degeneration and hearing loss concerning 24% of patients.
SCA7 is caused by a toxic polyglutamine expansion in Ataxin-7, a known subunit of the transcriptional co-regulator SAGA/TFTC complex. Transcriptional alterations are observed in SCA7, however, the disease mechanism is yet unclear. Ataxin-7 is also present in the cytoplasm of neurons, where its function is unknown.
Here, we show for the first time that Ataxin-7 is a bona fide component of centrosomes and is present in diverse types of mammalian cilia, including primary, motile and photoreceptor sensory cilia. We provide evidence that Ataxin-7 loss of function causes a large spectrum of ciliary-related morphological and functional phenotypes in zebrafish, and that human Ataxin-7 is able to rescue the cilia phenotypes, demonstrating that Ataxin-7 has an essential, evolutionarily conserved function in cilia. Strikingly, Ataxin-7 is progressively lost from photoreceptor cilia in SCA7 mouse models, correlating with ciliary defects and photoreceptor degeneration. Finally, we found that expression of polyQ-expanded Ataxin-7, like Ataxin-7 loss of function, leads to ciliary dysfunctions in zebrafish. Our study thus provides new insight into the function of Ataxin-7 and opens novel perspective in the understanding of SCA7 pathogenesis.
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.