Abstract
Depletion of yeast/fly Ataxin-2 rescues TDP-43 overexpression toxicity. In mouse models of Amyotrophic Lateral Sclerosis via TDP-43 overexpression, depletion of its ortholog ATXN2 mitigated motor neuron degeneration and extended lifespan from 25 days to >300 days. There is another ortholog in mammals, named ATXN2L (Ataxin-2-like), which is almost uncharacterized but also functions in RNA surveillance at stress granules. We generated mice with Crispr/Cas9-mediated deletion of Atxn2l exons 5-8, studying homozygotes prenatally and heterozygotes during aging. Our novel findings indicate that ATXN2L absence triggers mid-gestational embryonic lethality, affecting female animals more strongly. Weight and development stages of homozygous mutants were reduced. Placenta phenotypes were not apparent, but brain histology showed lamination defects and apoptosis. Aged heterozygotes showed no locomotor deficits or weight loss over 12 months. Null mutants in vivo displayed compensatory efforts to maximize Atxn2l expression, which were prevented upon nutrient abundance in vitro. Mouse embryonal fibroblast cells revealed more multinucleated giant cells upon ATXN2L deficiency. In addition, in human neural cells, transcript levels of ATXN2L were induced upon starvation and glucose and amino acids exposure, but this induction was partially prevented by serum or low cholesterol administration. Neither ATXN2L depletion triggered dysregulation of ATXN2, nor a converse effect was observed. Overall, this essential role of ATXN2L for embryogenesis raises questions about its role in neurodegenerative diseases and neuroprotective therapies.
Highlights
IntroductionAt least one copy of the Ataxin-2 gene (gene symbol ATXN2 in humans) is phylogenetically conserved and serves roles during nutrient stress for RNA surveillance [1]
In all eukaryotic organisms, at least one copy of the Ataxin-2 gene is phylogenetically conserved and serves roles during nutrient stress for RNA surveillance [1]
Working at cell culture level, we examined the cellular phenotype of Atxn2l−/− mouse embryonal fibroblasts (MEF), and whether the regulation of human ATXN2L and ATXN2 mRNA levels is similar in response to stressors for neural cells
Summary
At least one copy of the Ataxin-2 gene (gene symbol ATXN2 in humans) is phylogenetically conserved and serves roles during nutrient stress for RNA surveillance [1]. The RNA surveillance function of Ataxin-2 seems to be relevant to protect against the translation of viral RNAs, given that poliovirus is optimized to cleave Ataxin-2 [8] In mammals, all these protein structure domains are found in its paralog Ataxin-2-like (gene symbol ATXN2L in humans). The common ancestor of both proteins in yeast and Caenorhabditis elegans was observed to suppress growth signaling via mTORC1, modulating cell size, and lipid stores [13,14,15] This reprogramming of nutrient metabolism is accompanied by an important influence on the mitochondrial breakdown of fatty acids and amino acids, as well as glucose utilization [16,17,18,19], probably mediated by the direct protein interaction of ATXN2 with the cytosolic enzyme BCAT1 [20] as the rate-limiting factor in the breakdown of leucine, isoleucine, and valine
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