Biology subjects

Herrera-Rodriguez, R.

Publications and source records attributed to Herrera-Rodriguez, R..

3 recordsLinked to original sources

bioRxiv2026

Attenuating LRRK2 activity ameliorates progerin-induced aging phenotypes in HGPS models and during physiological aging

Hutchinson-Gilford progeria syndrome (HGPS) is an ultra-rare premature aging disorder caused by progerin, a truncated lamin A variant generated by a silent de novo mutation activating a cryptic splice site in LMNA. The resulting morphological, epigenetic, genomic, and proteostasic defects closely recapitulate some hallmarks of cellular aging. Here, we identify the Parkinsons disease-associated kinase LRRK2 as a critical regulator of HGPS pathology and physiological aging. Rab29-mediated LRRK2 hyperactivation exacerbates progerin-induced cellular aging, whereas LRRK2 knockdown or overexpression of its opposing phosphatase, PPM1H, ameliorates progerin-induced defects. Progerin-expressing cells exhibit altered intracellular trafficking, which is regulated by LRRK2 and links diverse aging hallmarks. Consistent with these findings, reducing LRRK2 levels mitigates cellular aging phenotypes in physiologically aged cells, and loss of the C. elegans ortholog lrk-1 preserves aging-associated loss of motility and extends organismal lifespan. Together, our findings establish LRRK2 as a central node in cellular aging and position it as a potential therapeutic target for aging-related defects in both HGPS and physiological aging.

cell biology↗

bioRxiv2026

Correcting Preprocessing Bias in Sparse Chromatin Contact Data Enables Physically Interpretable Reconstruction of Genome Architecture

DNA is the largest biopolymer in nature, and chromatin contact maps are widely interpreted as quantitative readouts of its three-dimensional organization. However, the validity of such interpretations critically depends on how these maps are processed. Here, we identify a previously overlooked but fundamental source of bias in chromatin contact data analysis. We demonstrate that a widely adopted preprocessing convention, namely whole-matrix percentile clipping, systematically distorts sparse contact maps by collapsing their dynamic range. This effect is strongest in near-diagonal interactions, precisely the regime encoding chromatin domains and looping structures, thereby compromising quantitative interpretation while preserving superficial structural features. We show that this distortion represents a sparsity-dependent failure mode of current preprocessing standards and affects the comparability of datasets and computational methods across technologies and sequencing depths. To address this, we introduce a statistically consistent preprocessing framework based on nonzero-percentile clipping and log-space normalization, which preserves the intrinsic dynamic range of observed contacts. Building on this foundation, we present CCUT, a modular deep learning framework for chromatin contact map reconstruction. Under corrected preprocessing, reconstructed maps recover domain organization, contact decay, and scaling behavior consistent with polymer physics. Importantly, we demonstrate quantitative agreement between reconstructed maps and simulated contact patterns derived from a kinetic Monte Carlo loop extrusion model, enabling direct comparison between experimental data and physical models. Together, our results establish preprocessing as a decisive determinant of the physical interpretability of chromatin contact maps and provide a principled framework for robust and comparable analysis across chromatin conformation capture technologies.

biophysics↗

bioRxiv2022

Nitric oxide-induced tyrosine nitration of TrkB impairs BDNF signaling and restrains neuronal plasticity

Nitric oxide has been long recognized as an important modulator of neural plasticity, but characterization of the molecular mechanisms involved - specially the guanylyl cyclase-independent ones - has been challenging. There is evidence that NO could modify BDNF-TRKB signaling, a key mediator of neuronal plasticity. However, the mechanism underlying the interplay of NO and TRKB remains unclear. Here we show that nitric oxide induces nitration of the tyrosine 816 in the TRKB receptor in vivo and in vitro, and that post-translational modification inhibits TRKB phosphorylation and binding of phospholipase C{gamma}1 (PLC{gamma}1) to this same tyrosine residue. Additionally, nitration triggers clathrin-dependent endocytosis of TRKB through the adaptor protein AP2M and ubiquitination, thereby increasing translocation of TRKB away from the neuronal surface and directing it towards lysosomal degradation. Accordingly, inhibition of nitric oxide increases TRKB phosphorylation and TRKB-dependent neurite branching in neuronal cultures. In vivo, chronic inhibition of neuronal nitric oxide synthase (nNOS) dramatically reduced TRKB nitration and facilitated TRKB signaling in the primary visual cortex, and promoted a shift in ocular dominance upon monocular deprivation in the visual cortex - an indicator of increased plasticity. Altogether, our data describe and characterize a new molecular brake on plasticity, namely nitration of TRKB receptors. Significance statementWe described the nitration of TRKB receptors at the tyrosine residue 816 as a new post-translational modification (PTM) that restrains the signaling of the neurotrophic factor BDNF in neurons. This new PTM leads to endocytosis and degradation of the TRKB receptors. Intriguingly, this mechanism is tonically active under physiological conditions in vivo, and it is important for restricting ocular dominance plasticity in the visual cortex. This mechanism directly links two major systems involved in brain plasticity, BDNF/TRKB and nitric oxide. Our data provides a model for how NO production from nNOS can compromise TRKB function, and for the effects of nNOS inhibitors promoting plasticity.

neuroscience↗