Ataxin-2 is essential for cytoskeletal dynamics and neurodevelopment in Drosophila

Abstract

Ataxin-2 (Atx2) is a highly conserved RNA binding protein. Atx2 undergoes polyglutamine expansion leading to Amyotrophic Lateral Sclerosis (ALS) or Spinocerebellar Ataxia (SCA). However, the normal physiological functions of Atx2 remain unknown, likely because of functional redundancy between Atx2 and the related Atx2-Like gene in mammals. Here we use the powerful genetics of Drosophila to show that Atx2 is essential for normal cytoskeletal dynamics in neurons. Neuron-specific depletion of Atx2 caused multiple morphological defects in the nervous system of 3rd instar larvae. These include reduced brain size, impairments in optic lobe innervation and decreased dendrite outgrowth in sensory neurons. Defects in the nervous system of these larvae caused loss of the ability to crawl and were lethal at the pupal stage. Interestingly, we found severe impairments in cytoskeletal dynamics both in microtubule and actin networks. Microtubules became hyperstabilized as demonstrated by increased tubulin acetylation and resistance to microtubule depolymerizing drugs. Similarly, we found F-actin was hyperstabilized as shown by resistance to depolymerizing agents. Further, we show inhibition of microtubule-microtubule sliding, a crucial process for initial neurite outgrowth. We also demonstrated that microtubule-dependent transport of multiple cargoes in neurons, both in vitro and in vivo, was dramatically inhibited. Taken together, these data mark Atx2 as a master regulator of cytoskeletal dynamics and denote Atx2 as an essential gene in neurodevelopment, as well as a neurodegenerative factor. These data could provide insight into potential therapeutic interventions for Atx2 polyglutamine disorders.Significance StatementNeurons extend a complex array of axons and dendrites for network formation and communication. Therefore, precise neuronal development is essential for normal nervous system function and viability. Neuronal development is highly dependent upon dynamics of the actin and microtubule cytoskeleton for extension and maintenance of neurites. There are many descriptions of cytoskeleton impairment in neurodegenerative disease, however, the physiological functions of many genes mutated in neurodegenerative remain undescribed. The major finding of this work is that the loss of Ataxin-2 at early developmental stages in Drosophila is lethal and causes multiple defects in neurodevelopment via dysregulation of the cytoskeleton.

Ataxin-2 gene: a powerful modulator of neurological disorders

“…ATXN2 is essential for neurodevelopment in Drosophila [11]. Both ATXN2 levels and its subcellular location determine the spacing of dendritic branches for the optimal dendritic receptive fields in sensory neurons in Drosophila [12].…”