AUTS2 Syndrome: Molecular Mechanisms and Model Systems.

AUTS2 syndrome is a genetic disorder that causes intellectual disability, microcephaly, and other phenotypes. Syndrome severity is worse when mutations involve 3' regions (exons 9-19) of the AUTS2 gene. Human AUTS2 protein has two major isoforms, full-length (1259 aa) and C-terminal (711 aa), the latter produced from an alternative transcription start site in exon 9. Structurally, AUTS2 contains the putative "AUTS2 domain" (∼200 aa) conserved among AUTS2 and its ohnologs, fibrosin, and fibrosin-like-1. Also, AUTS2 contains extensive low-complexity sequences and intrinsically disordered regions, features typical of RNA-binding proteins. During development, AUTS2 is expressed by specific progenitor cell and neuron types, including pyramidal neurons and Purkinje cells. AUTS2 localizes mainly in cell nuclei, where it regulates transcription and RNA metabolism. Some studies have detected AUTS2 in neurites, where it may regulate cytoskeletal dynamics. Neurodevelopmental functions of AUTS2 have been studied in diverse model systems. In zebrafish, auts2a morphants displayed microcephaly. In mice, excision of different Auts2 exons (7, 8, or 15) caused distinct phenotypes, variously including neonatal breathing abnormalities, cerebellar hypoplasia, dentate gyrus hypoplasia, EEG abnormalities, and behavioral changes. In mouse embryonic stem cells, AUTS2 could promote or delay neuronal differentiation. Cerebral organoids, derived from an AUTS2 syndrome patient containing a pathogenic missense variant in exon 9, exhibited neocortical growth defects. Emerging technologies for analysis of human cerebral organoids will be increasingly useful for understanding mechanisms underlying AUTS2 syndrome. Questions for future research include whether AUTS2 binds RNA directly, how AUTS2 regulates neurogenesis, and how AUTS2 modulates neural circuit formation

A Comprehensive Analysis of Replicative Lifespan in 4,698 Single-Gene Deletion Strains Uncovers Conserved Mechanisms of Aging

Many genes that affect replicative lifespan (RLS) in the budding yeast Saccharomyces cerevisiae also affect aging in other organisms such as C. elegans and M. musculus. We performed a systematic analysis of yeast RLS in a set of 4,698 viable single-gene deletion strains. Multiple functional gene clusters were identified, and full genome-to-genome comparison demonstrated a significant conservation in longevity pathways between yeast and C. elegans. Among the mechanisms of aging identified, deletion of tRNA exporter LOS1 robustly extended lifespan. Dietary restriction (DR) and inhibition of mechanistic Target of Rapamycin (mTOR) exclude Los1 from the nucleus in a Rad53-dependent manner. Moreover, lifespan extension from deletion of LOS1 is nonadditive with DR or mTOR inhibition, and results in Gcn4 transcription factor activation. Thus, the DNA damage response and mTOR converge on Los1-mediated nuclear tRNA export to regulate Gcn4 activity and aging