Biology subjects

Figueiredo, A. S.

Publications and source records attributed to Figueiredo, A. S..

4 recordsLinked to original sources

bioRxiv2025

The AUUUC repeat RNA aggregates sequester RNA-binding proteins like NOVA2 and lead to iron dyshomeostasis in spinocerebellar ataxia type 37

Transcribed nucleotide repeat expansions can contribute to disease by altering RNA structure and function. Spinocerebellar ataxia type 37 (SCA37) is a neurodegenerative disorder caused by a pathogenic ATTTC repeat insertion within a non-pathogenic ATTTT repeat in the 5 untranslated region of DAB1. We have shown that the AUUUC repeat RNA forms aberrant nuclear aggregates in cells, subsequently confirmed by others in neurons from subjects with familial adult myoclonic epilepsy carrying a similar ATTTC repeat insertion. However, the mechanism by which these RNA aggregates cause neuropathology remains unknown. Here, we show that overexpression of the ATTTC repeat in human neural stem cells leads to the formation of abnormal nuclear RNA aggregates, supporting an AUUUC repeat-mediated mechanism of pathology through the sequestration of RNA-binding proteins (RBP). We identified 12 AUUUC repeat-interacting RBPs with specific neuronal functions, including NOVA2, which we demonstrate to colocalize with the AUUUC repeat aggregates. Moreover, we further investigated the accumulation of iron in these aggregates and observed a significant colocalization of iron and NOVA2 hotspots in ATTTC repeat-expressing cells, a pattern absent in control cells. Together, these findings uncover a novel RNA-mediated mechanism of pathology involving both RBPs and iron, expanding the current understanding of RNA repeat toxicity.

cell biology↗

bioRxiv2025

Embryonic Spinocerebellar Ataxia Type 37 AUUUC Repeat RNA Causes Neurodevelopmental Defects in Zebrafish

Onset of many neurodegenerative and neuromuscular diseases usually starts in adulthood; however, recent advances point toward neurodevelopmental changes as drivers of late neurodegeneration. How early neuropathological features occur in these conditions remains unclear, which is critical for timely therapeutic intervention. Here, we provide evidence that neurodevelopmental axonal defects initiate a motor phenotype in a zebrafish model of spinocerebellar ataxia type 37 (SCA37), a degenerative hereditary condition caused by an ATTTC repeat in the DAB1 gene. We investigated neuronal defects triggered by the embryonic AUUUC repeat RNA and their effects later in life by transiently expressing this RNA in embryos and analyzing innervation and motor function. We found abnormalities in motor neuron axonal outgrowth and muscle innervation. We also discovered disrupted embryonic motor activity and reduced locomotor distance and velocity in late adult zebrafish, demonstrating motor impairment. Moreover, we showed that NOVA2 expression rescues axonal defects, indicating dysfunction of NOVA2-regulated neurodevelopmental processes. Overall, our results establish embryonic expression of the AUUUC repeat RNA as a driver of axonal and synaptic abnormalities, interfering with neuronal circuits and culminating in adult motor dysfunction.

neuroscience↗

bioRxiv2025

The Insertion of an ATTTC Repeat in an Alu Element Hyperactivates a Primate-Specific Neurodevelopmental Enhancer in Spinocerebellar Ataxia Type 37

Alu are evolutionarily very old primate-specific interspersed repeat elements that constitute [~]11% of the human genome. They are a source of short tandem repeats (STRs), which often expand in size and originate inherited neuromuscular and neurodegenerative disorders. How expanded STR insertion mutations within Alu STRs culminate in disease remains unknown. Here we report an Alu STR located in an intron of DAB1 that functions as a neurodevelopmental enhancer. We demonstrated that an ATTTC repeat insertion in this DAB1 Alu STR, known to cause spinocerebellar ataxia type 37 (SCA37), hyperactivates a neurodevelopmental DAB1 enhancer. Importantly, we showed that neurons derived from SCA37 subjects have higher levels of DAB1 expression and DAB1 overexpression causes abnormal axonal pathfinding in vivo. Overall, these results establish that neuronal dysregulation of a developmental DAB1 Alu STR enhancer contributes to SCA37 pathogenesis, an unexplored mechanism likely acting in many Alu STR diseases, potentially reshaping the therapeutic landscape.

genetics↗

bioRxiv2020

A 21-year survey of from bloodstream infections (BSIs) in a tertiary hospital reveals how community-hospital dynamics, influence local BSI rates, the trends of the B2 phylogroup and the STc131 pandemic clone

This is a longitudinal study comprising 649 Escherichia coli (EC) isolates representing all 7165 EC-BSI episodes recorded in a hospital (1996-2016). Strains analysis included clonal identification (phylogenetic groups/subgroups, STc131 subclades, PFGE, and WGS), antibiotic susceptibility (13 antibiotics), and virulence-associated genes (VAGs, 29 genes). The incidence of BSI-EC increased from 1996 to 2016 (5.5 to 10.8 BSI episodes/1000 hospitalizations, average 7-8/1000). B2 isolates predominate (53%), subgroups B2-I (STc131), B2-II, B2-IX, and B2-VI representing 25%, 25%, 14%, and 9%, respectively. Intertwined waves of community-acquired (CA) + healthcare-associated and community-onset healthcare-associated (HCA), and hospital-acquired (HA) episodes of both B2 and non-B2 phylogroups occurred. A remarkable increase was only observed for B2-I-STc131 (C1/C2 subclades), with oscillations for other B2 subgroups and phylogroups throughout the years. Epidemic and persistent clones (comprising isolates with highly similar/identical-PFGE types and genomes differing in 18-97 SNPs) of B2-I (STc131), B2-II (STc73), B2-III (STc127), B2-IX (STc95), and B2-VI (STc12) were recovered from different patients, most at hospital admission, for long periods (2-17 years), ESBL producers or resistance to ciprofloxacin in B2 isolates were almost restricted to B2-I (STc131) subclade C. STc131 contributed to increasing the B2 rates but only transiently altered the EC-population structure. The increase of EC-BSI was determined by waves of CA+HCA-BSI episodes that predate the waves of HA-BSI. Besides the risk of hospital transmission that led to temporal increases in BSIs, this study suggests that EC-populations/clones from community-based healthy individuals may occasionally have an epidemic structure and provide a source of transmissible strains influencing the HA-BSIs incidence. IMPORTANCESepsis is the third cause of mortality in Western countries and one of the Global Health threads recognized by the WHO since 2017. Despite Escherichia coli constitutes the most common cause of bloodstream infections (BSI), its epidemiology is not fully understood, in part due to the scarcity of local and longitudinal studies. Our work analyzes the long-term dynamics of E. coli causing bacteremia in a single institution and reveals waves of different clonal lineages that emerge periodically and successfully spread afterward in both the community and hospitals. Because the origin of BSI-E. coli infections is the gut, the microbiota of healthy individuals might occasionally have an epidemic structure, providing a source of E. coli strains to influence the incidence of hospital BSIs. The study complements previous fractionated observations focusing on specific E. coli lineages or antibiotic-resistant isolates in the last decades and helps to understand the epidemiology of E. coli BSIs and the dynamics of pandemic clones.

microbiology↗