Abstract
Expansion of a CAG repeat in ATXN3 causes the dominant polyQ disease Spinocerebellar ataxia type 3 (SCA3), yet the physiological role of ATXN3 remains unclear. We focused on the function of ATXN3 in the retina, a relevant neurological organ amenable to morphological and physiological studies. We show that depletion of Atxn3 in zebrafish and mice causes retinal morphological and functional alterations with photoreceptor outer segment elongation, cone opsin mislocalisation, and cone hyperexcitation. A pool of ATXN3 resides at the basal body and axoneme of the photoreceptor cilium, where it controls the levels and recruitment of the regulatory proteins KEAP1 and HDAC6. Abrogation of Atxn3 expression causes delayed phagosome maturation in the retinal pigment epithelium. We propose that ATXN3 regulates two relevant biological processes in the retina, ciliogenesis and phagocytosis, by modulating microtubule polymerization and microtubule-dependent retrograde transport, thus positing ATXN3 as a causative or modifier gene in retinal/macular dystrophies.
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