Biology subjects

Hacker, D.

Publications and source records attributed to Hacker, D..

5 recordsLinked to original sources

bioRxiv2026

SHANK3-CAMSAP2 interaction links synapses to dendritic microtubule organisation in PV neurons

The microtubule cytoskeleton plays an essential role in establishing and maintaining neuronal polarity. In neurons, microtubules are initially generated at the centrosome which gradually loses this role in development. In mature neurons, microtubules are stabilised by the microtubule minus end-binding protein CAMSAP2. How and where microtubule minus ends are anchored within dendrites of mammalian neurons remains an open question. Here, we show that microtubules are directly attached to the postsynaptic density of excitatory synapses through an interaction of CAMSAP2 with the scaffolding protein SHANK3. This process is particularly relevant in parvalbumin-positive GABAergic neurons, in which excitatory synapses are predominantly located directly on the dendritic shaft in direct proximity to microtubules. Notably, this association is strongly enhanced by the Autism Spectrum Disorder (ASD)-associated SHANK3L68P mutation, leading to an increase of synaptic levels of CAMSAP2. This promotes an increased microtubule association with the synapse and alters microtubule dynamics. Downregulation of CAMSAP2 in SHANK3L68P parvalbumin neurons tips the balance between site-specific microtubule stabilisation and dynamics, reshaping dendritic architecture, connecting SHANK3-CAMSAP2 dependent microtubule regulation to synaptic ASD pathology. TeaserInteraction between synapses and microtubules is enhanced in parvalbumin neurons bearing the ASD-associated SHANK3 L68P mutation.

neuroscience↗

bioRxiv2025

The Molecular Architecture of Somatic Spines of the Lateral Septum

The lateral septum is a key subcortical structure and has been implicated in kinship memory. Across species, the ability to recognise relatives is conserved and is reflected in stable, lifelong memories. The molecular mechanisms underlying kinship memory remain elusive. Here we investigate the synaptic architecture of septal circuits and focus on somatic spines, an apparent synaptic specialisation of this mainly GABAergic structure. We uncover the molecular organisation of septal somatic spines found in the lateral septum using a combination of unbiased imaging methods and confocal microscopy. We used classical label-free methods such as transmission electron microscopy and Golgi stainings and established new culturing methods for dissociated and organotypic septal slice cultures that were kept in culture over multiple weeks. We describe the presence, morphology, ultrastructure and molecular composition of excitatory somatic spines across multiple developmental stages in various model systems. While smaller than dendritic spines, somatic spines exhibited distinct features, frequently containing secretory organelles such as phagophores and endosomes, but often lack a spine apparatus and ribosomes. Our findings offer insights on the molecular architecture of septal somatic spines and establish a basis for further investigations on the somatic spines of the lateral septum and their role in kinship memory. Significance statementSpine synapses represent stable synaptic connections that allow neurons to chemically communicate with each other. Although known for decades, the unusual spine synapses found directly on neuronal cell bodies in the lateral septum have not been characterised in detail. Using traditional, unbiased approaches such as electron microscopy and Golgi stainings, we replicate the initial findings. Additionally, using fluorescent microscopy of dissociated and organotypic septal cultures, we characterise the development and composition of septal somatic spines. We find that they are excitatory, contain membranous organelles and develop independently of extra-septal input. We thus describe model systems suitable for the investigation of somatospiny neurons of the lateral septum.

neuroscience↗

bioRxiv2020

Structural investigation of ACE2 dependent disassembly of the trimeric SARS-CoV-2 Spike glycoprotein

The human membrane protein Angiotensin-converting enzyme 2 (hACE2) acts as the main receptor for host cells invasion of the new coronavirus SARS-CoV-2. The viral surface glycoprotein Spike binds to hACE2, which triggers virus entry into cells. As of today, the role of hACE2 for virus fusion is not well understood. Blocking the transition of Spike from its prefusion to post-fusion state might be a strategy to prevent or treat COVID-19. Here we report a single particle cryo-electron microscopy analysis of SARS-CoV-2 trimeric Spike in presence of the human ACE2 ectodomain. The binding of purified hACE2 ectodomain to Spike induces the disassembly of the trimeric form of Spike and a structural rearrangement of its S1 domain to form a stable, monomeric complex with hACE2. This observed hACE2 dependent dissociation of the Spike trimer suggests a mechanism for the therapeutic role of recombinant soluble hACE2 for treatment of COVID-19.

biophysics↗

bioRxiv2020

Immune response to vaccine candidates based on different types of nanoscaffolded RBD domain of the SARS-CoV-2 spike protein

Effective and safe vaccines against SARS-CoV-2 are highly desirable to prevent casualties and societal cost caused by Covid-19 pandemic. The receptor binding domain (RBD) of the surface-exposed spike protein of SARS-CoV-2 represents a suitable target for the induction of neutralizing antibodies upon vaccination. Small protein antigens typically induce weak immune response while particles measuring tens of nanometers are efficiently presented to B cell follicles and subsequently to follicular germinal center B cells in draining lymph nodes, where B cell proliferation and affinity maturation occurs. Here we prepared and analyzed the response to several DNA vaccines based on genetic fusions of RBD to four different scaffolding domains, namely to the foldon peptide, ferritin, lumazine synthase and {beta}-annulus peptide, presenting from 6 to 60 copies of the RBD on each particle. Scaffolding strongly augmented the immune response with production of neutralizing antibodies and T cell response including cytotoxic lymphocytes in mice upon immunization with DNA plasmids. The most potent response was observed for the 24-residue {beta}-annulus peptide scaffold that forms large soluble assemblies, that has the advantage of low immunogenicity in comparison to larger scaffolds. Our results support the advancement of this vaccine platform towards clinical trials.

immunology↗

bioRxiv2017

Intra- and inter-chromosomal chromatin interactions mediate genetic effects on regulatory networks

Genome-wide studies on the genetic basis of gene expression and the structural properties of chromatin have considerably advanced our understanding of the function of the human genome. However, it remains unclear how structure relates to function and, in this work, we aim at bridging both by assembling a dataset that combines the activity of regulatory elements (e.g. enhancers and promoters), expression of genes and genetic variations of 317 individuals and across two cell types. We show that the regulatory activity is structured within 12,583 Cis Regulatory Domains (CRDs) that are cell type specific and highly reflective of the local (i.e. Topologically Associating Domains) and global (i.e. A/B nuclear compartments) nuclear organization of the chromatin. These CRDs essentially delimit the sets of active regulatory elements involved in the transcription of most genes, thereby capturing complex regulatory networks in which the effects of regulatory variants are propagated and combined to finally mediate expression Quantitative Trait Loci. Overall, our analysis reveals the complexity and specificity of cis and trans regulatory networks and their perturbation by genetic variation.

genomics↗