Biology subjects

Rubio Sanchez, R.

Publications and source records attributed to Rubio Sanchez, R..

2 recordsLinked to original sources

bioRxiv2023

The C9Orf72 hexanucleotide repeat expansion transcript forms insoluble aggregates facilitated by multimolecular G-quadruplex structures

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases that exist on a clinico-pathogenetic spectrum, designated ALS/FTD. The most common genetic cause of ALS/FTD is the expansion of the intronic hexanucleotide repeat (GGGGCC)nin C9orf72. Here, we investigated the formation of nucleic-acid secondary structures in these expansion repeats, and their role in generating condensates characteristic of the diseases. We observed significant aggregation of the hexanucleotide sequence (GGGGCC)n, which we associated to the formation of multimolecular G-quadruplexes (mG4s), using a range of biophysical techniques. Exposing the condensates to G4-unfolding conditions led to prompt disassembly, highlighting the key role of mG4-formation in the condensation process. We further validated the biological relevance of our findings by demonstrating the ability of a G4-selective fluorescent probe to penetrate C9orf72 mutant human motor neurons derived from ALS patients, which revealed clear fluorescent signal in putative condensates. Our findings strongly suggest that RNA G- rich repetitive sequences can form protein-free condensates sustained by multimolecular G- quadruplexes, highlighting their potential relevance as therapeutic targets for C9orf72 mutation related ALS and FTD. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=119 SRC="FIGDIR/small/526399v3_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@18c11e6org.highwire.dtl.DTLVardef@eb308eorg.highwire.dtl.DTLVardef@c0c870org.highwire.dtl.DTLVardef@a7555a_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2021

Thermal oscillations enable reshuffling of genetic material in a primitive cell cycle

Self-assembling single-chain amphiphiles available in the prebiotic environment likely played a fundamental role in the advent of primitive cell cycles. However, the instability of prebiotic fatty acid-based membranes to temperature and pH seems to suggest that primitive cells could only host prebiotically-relevant processes in a narrow range of non-fluctuating environmental conditions. Here we propose a novel primitive cell cycle driven by environmental fluctuations, which enable the generation of daughter protocells with reshuffled content. A reversible membrane-to-oil phase transition accounts for the dissolution of fatty acid-based vesicles at high temperatures, and the concomitant release of genetic content. At low temperatures, fatty acid bilayers reassemble and encapsulate reshuffled genetic material in a new cohort of protocells. Notably, we find that our disassembly/reassembly cycle drives the emergence of functional RNA-containing primitive cells from parent non-functional compartments. Thus, by exploiting the intrinsic instability of prebiotic fatty acid vesicles, our results point at an environmentally-driven tunable primitive cell cycle, which supports the release and reshuffle of protocellular genetic and membrane components, potentially leading to a new generation of protocells with superior traits. In the absence of protocellular transport machinery, the environmentally-driven disassembly/assembly cycle proposed herein would have supported genetic content reshuffling transmitted to primitive cell progeny, hinting at a potential mechanism important to initiate Darwinian evolution of early lifeforms.

biophysics↗