BIN1 expression in the presynaptic compartment leads to isoform-specific synaptotoxicity

Lambert, E.; Gelle, C.; Leclerc, V.; Freire-Regatillo, A.; Barois, N.; Malfoi, T.; Hermant, X.; Demiautte, F.; Lafont, F.; Amouyel, P.; Blary, K.; Kuenen, S.; Najdek, C.; Verstreken, P.; Siedlecki-Wullich, D.; Yger, P.; Lambert, J.-C.; Kilinc, D.; Dourlen, P.

doi:10.1101/2025.08.11.669624

bioRxiv · 10.1101/2025.08.11.669624

BIN1 expression in the presynaptic compartment leads to isoform-specific synaptotoxicity

Lambert, E.·Gelle, C.·Leclerc, V.·Freire-Regatillo, A.·Barois, N.·Malfoi, T.·Hermant, X.·Demiautte, F.·Lafont, F.·Amouyel, P.·Blary, K.·Kuenen, S.·Najdek, C.·Verstreken, P.·Siedlecki-Wullich, D.·Yger, P.·Lambert, J.-C.·Kilinc, D.·Dourlen, P.

View original source ↗Export metadata ↓

Abstract

Alzheimers disease (AD) is characterized by a strong genetic predisposition and by an early loss of synaptic connectivity that strongly correlates with cognitive deficit. Some genetic determinants could contribute to synapse frailty toward AD pathology. However, the role of genetic determinants in AD pathogenesis remains poorly understood at the synaptic level. Here, we show that the expression of an isoform of the major AD susceptibility gene BIN1 in the presynaptic compartment results in synaptic loss. Using electrophysiology, we observed an early loss of synaptic transmission upon BIN1 isoform 1 (BIN1iso1) expression in Drosophila retinal photoreceptor neurons. This was not observed for the other human BIN1 isoforms tested, isoform 8 and isoform 9. Structural analysis of photoreceptor neuron synapses shows a strong accumulation of abnormally large vesicles in the presynaptic compartment, reminiscent of this same isoform-induced endosome defects in cell bodies. In addition, the expression of BIN1iso1 in motoneurons of the Drosophila neuromuscular junction alters the morphology of synaptic boutons, with a greater number and a smaller size of synaptic boutons, and the appearance of satellite boutons. As opposed to endosomal defects in cell body, modulating the Rab11 recycling endosome regulator did not prevent BIN1iso1 synaptotoxicity. To test if synaptic deficits are conserved in a mammalian model and to assert a presynaptic vs postsynaptic role for BIN1, we used rat primary neurons cultured in microfluidic devices that restrict gene expression modulation in particular neuron populations. We found a loss of synaptic connectivity only when expressing BIN1iso1 in the presynaptic compartment, which was confirmed by microelectrode array analysis. Together, our results suggest that BIN1 expression in the presynaptic terminal, but not the postsynaptic terminal leads to an isoform-specific, deleterious effect on synaptic integrity. BIN1 synaptotoxicity could contribute to the synapse loss observed early in AD. This supports the idea that genetic determinants could make synapses prone to failure in AD.

Explore related subjects

neuroscience Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Lambert, E., Gelle, C., Leclerc, V., Freire-Regatillo, A., Barois, N., Malfoi, T., Hermant, X., Demiautte, F., Lafont, F., Amouyel, P., Blary, K., Kuenen, S., Najdek, C., Verstreken, P., Siedlecki-Wullich, D., Yger, P., Lambert, J.-C., Kilinc, D., Dourlen, P.. 2025-08-15. BIN1 expression in the presynaptic compartment leads to isoform-specific synaptotoxicity. https://doi.org/10.1101/2025.08.11.669624

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

The Unreasonable Effectiveness of Cell Types in Describing Neuronal Physiological Features

Single-cell RNA sequencing (scRNA-seq) captures detailed gene expression profiles at scale, while patch-clamp recordings measure intrinsic neuronal electrophysiological properties. Modeling the relations between these two modalities remains a challenge. Here, we compare how well electrophysiological features can be predicted by traditional transcriptomic cell type classification, representations derived from a foundational model (scGPT) pretrained on large-scale scRNA-seq datasets, ion channel-coding genes, and highly variable genes. Using paired transcriptomic and electrophysiological patch-sequencing data from 495 human neurons from neurosurgical tissue, we find that cluster-level cell type representations consistently outperform highly variable gene selection, ion channel gene selection, and context-enriched scGPT embeddings. Notably, performance varies across model architectures and initializations, and the best results are obtained by combining the outputs of separate cell type and scGPT-based models. Together, these findings suggest that traditional discrete cellular classification is highly effective in predicting physiological features. For maximum performance it can be complemented by pretrained transformer models.

neuroscience↗

bioRxiv2026

A nonlinear inhibition pathway underlying cortical responses to tuned holographic optogenetic perturbations

Optogenetics enables causal manipulation of cortical activity. Perturbation responses can be counterintuitive due to network interactions, making theory essential for predicting them. Existing approaches often rely on linear approximations, which fail for many biologically relevant perturbations. Here we develop a nonlinear theory of responses to holographic perturbations in cell-type-specific recurrent networks with structured connectivity. We fit a nonlinear model to mouse V1 data, which shows cotuned-ensemble suppression: perturbing spatially clustered neurons with similar preferred orientations yields markedly stronger short-range suppression than perturbing untuned ensembles. We show that cotuned-ensemble suppression arises from a feature-tuned, nonlinear inhibition pathway implicating somatostatin-positive (SST) interneurons. The theory predicts that cotuned ensembles suppress parvalbumin-positive (PV) neurons but facilitate SST neurons, and links the degree of cotuned-ensemble suppression or facilitation to the variance of the SST response. This framework identifies mechanisms by which nonlinear inhibition sculpts cortical dynamics and establishes a predictive basis for targeted optogenetic interventions.

neuroscience↗

bioRxiv2026

Proteomic signatures of APOE ε4 across human tissues and cell types in Alzheimers disease

The apolipoprotein E {varepsilon}4 (APOE {varepsilon}4) allele is the strongest genetic risk factor for late-onset Alzheimers disease (AD). However, the underlying molecular mechanisms remain unclear. This study included 1691 participants from the Religious Orders Study and Rush Memory and Aging Project (ROSMAP), 1226 participants from the Accelerating Medicines Partnership - Alzheimers Disease (AMP-AD) Diverse Cohorts Study, and 735 participants from the Alzheimers Disease Neuroimaging Initiative (ADNI). To characterise APOE {varepsilon}4 molecular effects, we analysed proteomic data from plasma, cerebrospinal fluid (CSF), and induced pluripotent stem cell (iPSC)-derived astrocytes and neurons, as well as transcriptomic and proteomic data from multiple brain regions. The association of APOE {varepsilon}4 with AD neuropathology was also examined. APOE {varepsilon}4 carriers shared a plasma proteomic signature enriched for immune processes, irrespective of AD diagnosis. A machine learning classifier trained on this signature discriminated APOE {varepsilon}4 carriers from non-carriers in an independent cohort using CSF proteomics. APOE {varepsilon}4 carriage was associated with higher Braak stages and Consortium to Establish a Registry for Alzheimers Disease (CERAD) score. However, only limited APOE {varepsilon}4-associated transcriptomic and proteomic changes were observed in bulk brain tissue, with poor cross-layer concordance. Proteomic analyses of iPSC-derived astrocytes and neurons further revealed cell-type-specific APOE {varepsilon}4-associated changes. APOE {varepsilon}4 is associated with a consistent proteomic signature across plasma and CSF. Its molecular effects in the brain differ across cell types, brain regions and molecular layers. These findings support the need for cell-type-resolved multi-omic studies to elucidate how APOE {varepsilon}4 confers AD risk.

neuroscience↗