Biology subjects

Zasso, J.

Publications and source records attributed to Zasso, J..

4 recordsLinked to original sources

bioRxiv2026

Insulin synthesis is sustained by Tent5 poly(A) polymerases

Insulin is an essential regulator of glucose homeostasis in vertebrates, and impairment of its synthesis or action leads to diabetes with severe health complications in humans. It is therefore essential to understand how beta cells control insulin synthesis and secretion, including the transcription, translation and decay of its messenger RNA. Using sequencing-based poly(A) tail length profiling from human tissue, genetic evidence for type 2 diabetes, bulk and single-cell transcriptomics and perturbation experiments, here we find that the insulin mRNA is stabilized by the activity of noncanonical poly(A) polymerases of the Tent5 family. We show that Tent5 activity is specific, promoted by both localization at the endoplasmic reticulum and regulatory sequences within the insulin mRNA and regulated by glucose. Overall, our findings provide a mechanistic link between the dynamic control of insulin production by beta cells and the direct regulation of insulin mRNA metabolism.

molecular biology↗

bioRxiv2021

Defective linear and circular RNAs biogenesis in Huntington's disease: CAG repeat expansion hijacks neuronal splicing

Alternative splicing (AS) appears to be altered in Huntingtons disease (HD), but its significance for early, pre-symptomatic disease stages has not been inspected. Here, taking advantage of Htt CAG knock-in mouse in vitro and in vivo models, we demonstrate a strong correlation between Htt CAG repeat length and increased aberrant linear AS, specifically affecting neural progenitors and, in vivo, the striatum prior to overt behavioral phenotypes stages. Remarkably, expanded Htt CAG repeats reflect on a previously neglected, global impairment of back-splicing, leading to decreased circular RNAs production in neural progenitors. Though the mechanisms of this dysregulation remain uncertain, our study unveils network of transcriptionally altered micro-RNAs and RNA-binding proteins (CELF, hnRNPS, PTBP, SRSF) which, in turn, might influence the AS machinery, primarily in neural cells. We suggest that this unbalanced expression of linear and circular RNAs might result in altered neural fitness, contributing to HD striatal vulnerability.

genetics↗

bioRxiv2020

One-shot analysis of translated mammalian lncRNAs with AHARIBO

A vast portion of the mammalian genome is transcribed as long non-coding RNAs (lncRNAs) acting in the cytoplasm with largely unknown functions. Surprisingly, lncRNAs have been shown to interact with ribosomes, encode uncharacterized proteins, or act as ribosome sponges. These functions still remain mostly undetected and understudied owing to the lack of efficient tools for genome-wide simultaneous identification of ribosome-associated lncRNAs and peptide-producing lncRNAs. Here we present AHARIBO, a method for the detection of lncRNAs either untranslated, but associated with ribosomes, or encoding small peptides. Using AHARIBO in mouse embryonic stem cells during neuronal differentiation, we isolated ribosome-protected RNA fragments, translated RNAs and corresponding de novo synthesized polypeptides. Besides identifying mRNAs under active translation and associated ribosomes, we found and distinguished lncRNAs acting as ribosome sponges or encoding micropeptides, laying the ground for a better functional understanding of hundreds lncRNAs.

cell biology↗

bioRxiv2018

Inducible alpha-synuclein overexpression affects human Neural Stem Cells behavior

Converging evidence suggest that levels of alpha-Synuclein (aSyn) expression play a critical role in Parkinsons disease (PD). Several mutations of the SNCA gene, encoding for aSyn have been associated to either the familial or the sporadic forms of PD. Nonetheless, the mechanism underlying wild type aSyn-mediated neurotoxicity in neuronal cells as well as its specific driving role in PD pathogenesis has yet to be fully clarified. In this view, the development of proper in vitro cellular systems is a crucial step.\n\nHere we present a novel human Tet-on hNSC cell line, in which aSyn timing and level of expression can be tightly experimentally tuned. Induction of aSyn in self-renewing hNSCs leads to progressive formation of aSyn aggregates and impairs their proliferation and cell survival. Furthermore, aSyn induction during the neuronal differentiation process results in impaired neurogenic potential due to enhanced refractoriness to exit self-renewal and to increase of gliogenic vs neurogenic competence. Finally, acute aSyn induction in hNSC-derived dopaminergic neuronal cultures results in cell toxicity.\n\nThis novel conditional in vitro cell model system may be a valuable tool for dissecting of aSyn pathogenic effects in hNSCs and neurons and in developing new potential therapeutic strategies.

neuroscience↗