Biology subjects

Brandi, L.

Publications and source records attributed to Brandi, L..

3 recordsLinked to original sources

bioRxiv2026

Co-option of CENP-A for activity-induced neuronal plasticity

Neuronal activation drives activity-dependent gene expression that underlies experience-associated synaptic modifications, learning and memory. Here we show that the histone variant CENP-A, best known for specifying centromere identity, is dynamically regulated by synaptic activity at both the RNA and protein levels in postmitotic neurons. Neuronal activation increases a non-centromeric nuclear pool of CENP-A while leaving centromeric CENP-A levels unchanged. Downregulation of CENP-A selectively reduces the activity-associated non-centromeric pool, impairs activity-dependent induction of immediate-early genes such as FOS and ARC, and disrupts hippocampus-dependent learning and memory. Furthermore, we find that activity-dependent neuronal responses in human embryonic stem cell-derived forebrain organoids similarly require CENP-A. Our results reveal a mitosis-independent, conserved role of CENP-A for driving plasticity in mammalian neurons.

neuroscience↗

bioRxiv2024

A binding site for the antibiotic GE81112 in the ribosomal mRNA channel

The initiation phase is the rate-limiting step of protein synthesis (translation) and is finely regulated, making it an important drug target. In bacteria, initiation is guided by three initiation factors and involves positioning the start site on the messenger RNA within the P-site on the small ribosomal subunit (30S), where it is decoded by the initiator tRNA. This process can be efficiently inhibited by GE81112, a natural hydrophilic, noncyclic, nonribosomal tetrapeptide. It is found in nature in three structural variants (A, B and B1 with molecular masses of 643-658 Da). Previous biochemical and structural characterisation of GE81112 indicates that the primary mechanism of action of this antibiotic is to (1) prevent the initiator tRNA from binding correctly to the P-site and (2) block conformational rearrangements in initiation factor IF3, resulting in an unlocked 30S preIC state. In this study, using cryoEM, we have determined the binding site of GE81112 in initiation complexes (3.2-3.7[A]) and on empty ribosomes (2.09 [A]). This binding site is within the mRNA channel (E-site) but remote from the binding site of the initiation factors and initiator tRNA. This suggests that it acts allosterically to prevent the initiator tRNA from being locked into place. The binding mode is consistent with previous biochemical studies and recent work identifying the key pharmacophores of GE81112.

microbiology↗

bioRxiv2024

TIAM1 signaling drives prostatic budding and branching phenotypes and is a potential therapeutic target for BPH

Benign prostatic hyperplasia (BPH) is the most prevalent urologic disease in men aged over 50 years. However, the molecular mechanisms that drive BPH pathophysiology remain elusive. In this study, we integrated bioinformatic and experimental analyses of human BPH to identify TIAM1-RAC1 signaling pathway as a promising candidate for a molecular-based approach for BPH therapy. First, elevated TIAM1 expression in a BPH transcriptomic signature that was generated from the analysis of RNA-seq data from three independent BPH patient cohorts was validated at the protein level in a fourth patient cohort. Additional bioinformatic analyses of the BPH transcriptomic signature pointed to TIAM1-RAC1 pathway as the potential lead therapeutic pathway; and NSC23766 - a small molecule inhibitor of TIAM1 signaling - as a developmental lead compound for BPH therapy. Next, a proof-of-concept pharmacological approach of TIAM1-RAC1 inhibition in human prostatic cells using NSC23766 resulted in attenuated organoid budding and branching - a developmental program associated with prostatic nodule formation and BPH pathogenesis. Finally, shRNA-based genetic knock-down of TIAM1 in human prostatic cells led to a reduction in budding and branching phenotypes thereby phenocopying the effects of NSC23766. Together, our observations implicate elevated TIAM1 as a driver of budding and branching in BPH, and our studies pave the way for TIAM1-RAC1 based targeted approach for the treatment of the disease.

cell biology↗