Departament de Genètica, Microbiologia i Estadística, Avda. Diagonal 643, Universitat de Barcelona, Barcelona 08028, Spain; CIBERER, ISCIII, Universitat de Barcelona, Barcelona, Spain; Department of Neurology, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA.
Departament de Genètica, Microbiologia i Estadística, Avda. Diagonal 643, Universitat de Barcelona, Barcelona 08028, Spain.
Cell Rep. 2020 Nov 10;33(6):108360. doi: 10.1016/j.celrep.2020.108360.
Expansion of a CAG repeat in ATXN3 causes the dominant polyglutamine disease spinocerebellar ataxia type 3 (SCA3), yet the physiological role of ATXN3 remains unclear. Here, we focus on unveiling the function of Ataxin-3 (ATXN3) in the retina, a neurological organ amenable to morphological and physiological studies. Depletion of Atxn3 in zebrafish and mice causes morphological and functional retinal alterations and, more precisely, photoreceptor cilium and outer segment elongation, cone opsin mislocalization, and cone hyperexcitation. ATXN3 localizes at the basal body and axoneme of the cilium, supporting its role in regulating ciliary length. Abrogation of Atxn3 expression causes decreased levels of the regulatory protein KEAP1 in the retina and delayed phagosome maturation in the retinal pigment epithelium. We propose that ATXN3 regulates two relevant biological processes in the retina, namely, 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.
ATXN3 中的 CAG 重复扩增会导致显性多聚谷氨酰胺疾病脊髓小脑共济失调 3 型（SCA3），但 ATXN3 的生理作用仍不清楚。在这里，我们专注于揭示 Ataxin-3（ATXN3）在视网膜中的功能，视网膜是一种适合形态学和生理学研究的神经器官。斑马鱼和小鼠中 Atxn3 的缺失会导致形态和功能上的视网膜改变，更确切地说，会导致光感受器纤毛和外节伸长、视锥蛋白错位和视锥细胞过度兴奋。ATXN3 定位于纤毛的基体和轴丝，支持其在调节纤毛长度中的作用。Atxn3 表达的缺失会导致视网膜中调节蛋白 KEAP1 的水平降低，并导致视网膜色素上皮中的吞噬体成熟延迟。我们提出，ATXN3 通过调节微管聚合和微管依赖性逆行运输，调节视网膜中的两个相关生物学过程，即纤毛发生和吞噬作用，从而将 ATXN3 作为视网膜/黄斑营养不良的致病或修饰基因。
