Publications

Prion-like domains (PrLDs) are intrinsically disordered regions (IDRs) of low sequence complexity with a similar composition to yeast prion domains. PrLDs-containing proteins have been involved in different organisms' regulatory processes. Regions of moderate amyloid propensity within IDRs have been shown to assemble autonomously into amyloid fibrils. These sequences tend to be rich in polar amino acids and often escape from the detection of classical bioinformatics screenings that look for highly aggregation-prone hydrophobic sequence stretches. We defined them as cryptic amyloidogenic regions (CARs) and recently developed an integrated database that collects thousands of predicted CARs in IDRs. CARs seem to be evolutionary conserved among disordered regions because of their potential to stablish functional contacts with other biomolecules. Here we have focused on identifying and characterizing CARs in prion-like proteins (pCARs) from plants, a lineage that has been poorly studied in comparison with other prionomes. We confirmed the intrinsic amyloid potential for a selected pCAR from Arabidopsis thaliana and explored functional enrichments and compositional bias of pCARs in plant prion-like proteins.Copyright © 2023 Pintado-Grima, Santos, Iglesias, Manglano-Artuñedo, Pallarès and Ventura.

JTD Keywords: aggregation, aromatic residues, bioinformatics, domains, functional interactions, identify proteins, plants, prediction, prion-like domains, q/n-rich, regulator, sup35, yeast, Bioinformatics, Cryptic amyloidogenic regions, Functional interactions, Plants, Prion-like domains, Rna-binding proteins

Axonal injury results in regenerative success or failure, depending on whether the axon lies in the peripheral or the CNS, respectively. The present study addresses whether epigenetic signatures in dorsal root ganglia discriminate between regenerative and non-regenerative axonal injury. Chromatin immunoprecipitation for the histone 3 (H3) post-translational modifications H3K9ac, H3K27ac and H3K27me3; an assay for transposase-accessible chromatin; and RNA sequencing were performed in dorsal root ganglia after sciatic nerve or dorsal column axotomy. Distinct histone acetylation and chromatin accessibility signatures correlated with gene expression after peripheral, but not central, axonal injury. DNA-footprinting analyses revealed new transcriptional regulators associated with regenerative ability. Machine-learning algorithms inferred the direction of most of the gene expression changes. Neuronal conditional deletion of the chromatin remodeler CCCTC-binding factor impaired nerve regeneration, implicating chromatin organization in the regenerative competence. Altogether, the present study offers the first epigenomic map providing insight into the transcriptional response to injury and the differential regenerative ability of sensory neurons.

JTD Keywords: Cell biology, Computational biology and bioinformatics, Molecular biology, Neuroscience

Insoluble protein aggregates are the hallmarks of many neurodegenerative diseases. For example, aggregates of TDP-43 occur in nearly all cases of amyotrophic lateral sclerosis (ALS). However, whether aggregates cause cellular toxicity is still not clear, even in simpler cellular systems. We reasoned that deep mutagenesis might be a powerful approach to disentangle the relationship between aggregation and toxicity. We generated >50,000 mutations in the prion-like domain (PRD) of TDP-43 and quantified their toxicity in yeast cells. Surprisingly, mutations that increase hydrophobicity and aggregation strongly decrease toxicity. In contrast, toxic variants promote the formation of dynamic liquid-like condensates. Mutations have their strongest effects in a hotspot that genetic interactions reveal to be structured in vivo, illustrating how mutagenesis can probe the in vivo structures of unstructured proteins. Our results show that aggregation of TDP-43 is not harmful but protects cells, most likely by titrating the protein away from a toxic liquid-like phase.

JTD Keywords: Computational biology and bioinformatics, Genomics, Mechanisms of disease, Neurodegeneration, Systems biology