Biology subjects

Alcala-Vida, R.

Publications and source records attributed to Alcala-Vida, R..

2 recordsLinked to original sources

bioRxiv2026

Dynamic Modulation of Neural Cell Identity Maintenance via Lysine Acetyltransferase Type 3 Protein Targeted Degradation

Cell identity acquisition during central nervous system development leads to the establishment of cell-specific transcriptional programs. Once acquired, this identity must be actively maintained, among other molecular mechanisms, by the acetylation of cell-type-specific regulatory regions carried out by the lysine acetyltransferases type 3 (KAT3) proteins CBP and p300. Here, we characterize the rapid transcriptional and physiological consequences of KAT3 elimination in neuronal and glial lineages by means of a KAT3-specific PROTAC degrader, providing strong evidence for their central role as neural identity wardens. Importantly, the restoration of KAT3 proteins in glial cells after cell identity erasure resulted in the recovery of the original transcriptome and physiological functions, probing the dynamic nature of neural cell identities. These findings expand the role of CBP/p300 as identity wardens and challenge our perception of terminal cellular identities as static irrevocable states, opening new avenues for neural identity manipulation with biomedical purposes.

neuroscience↗

bioRxiv2020

Neuron-specific increase in lamin B1 disrupts nuclear function in Huntington's disease

Lamins are crucial proteins for nuclear functionality. Here, we provide new evidence showing an involvement of increased lamin B1 levels in the pathophysiology of Huntingtons disease (HD), a CAG repeat-associated neurodegenerative disorder. Through fluorescence-activated nuclear suspension imaging we demonstrate that nucleus from striatal medium-sized spiny and CA1 hippocampal neurons display increased lamin B1 levels, in correlation with altered nuclear morphology and nucleocytoplasmic transport disruption. Moreover, ChIP-sequencing analysis shows an alteration of lamin-associated chromatin domains in hippocampal nuclei, which could contribute to transcriptional alterations we determined by RNA sequencing. Supporting lamin B1 alterations as a causal role in mutant-huntingtin mediated neurodegeneration, pharmacological normalization of lamin B1 levels by betulinic acid administration in the R6/1 mouse model of HD restored nuclear homeostasis and prevented motor and cognitive dysfunction. Collectively, our work point out increased lamin B1 levels as a new pathogenic mechanism in HD and provides a novel target for its intervention.

neuroscience↗