Biology subjects

van der Spek, S.

Publications and source records attributed to van der Spek, S..

3 recordsLinked to original sources

bioRxiv2025

Progressive Remodeling of Global Protein Interaction Networks in a Mouse Model of Tauopathy

Neurodegenerative disease is marked not just by loss of proteins or cells, but by dynamic rewiring of macromolecular interaction networks that precede and drive pathology. Here, we present the first temporally resolved, systems-scale map of multi-protein complex remodeling in a tauopathy model, integrating co-fractionation mass spectrometry, quantitative phosphoproteomics, and machine learning to decode phosphorylation-dependent shifts in protein interactomes across disease progression. This interactomic atlas identifies functionally validated assemblies--including MAPT-Dpysl2 and Cyfip1-actin complexes--that modulate early disease phenotypes in vivo. By revealing how phosphorylation tunes macromolecular complex architecture and function, this work reframes tauopathy as a disease of dynamic network instability, and establishes a generalizable framework for early detection and mechanistic dissection of neurodegeneration.

neuroscience↗

bioRxiv2022

Transcriptional diversity in synaptic gene sets is sufficient to discriminate cortical neuronal identity

Synapse diversity has been described from different perspectives, ranging from the specific neurotransmitters released, to their diverse biophysical properties and proteome profiles. However, synapse diversity at the transcriptional level has not been systematically identified across all synapse populations in the brain. To quantify postsynaptic and identify specific synaptic features of neuronal cell types we combined the SynGO (Synaptic Gene Ontology) database with single-cell RNA sequencing data of the mouse neocortex. We show that cell types can be discriminated by synaptic genes alone with the same power as all genes. The cell type discriminatory power is not equally distributed across synaptic genes as we could identify functional categories and synaptic compartments with greater cell type specific expression. Synaptic genes, and specific SynGO categories, belonged to three different types of gene modules: gradient expression over all cell types, gradient expression in selected cell types and cell class- or type-specific profiles. This data provides a deeper understanding of synapse diversity in the neocortex and identifies potential markers to selectively identify synapses from specific neuronal populations.

neuroscience↗

bioRxiv2021

β-amyloid-driven synaptic depression requires PDZ protein interaction at AMPA-receptor subunit GluA3

Soluble oligomeric amyloid-{beta} (A{beta}) is a prime suspect to cause cognitive deficits in Alzheimers disease and weakens synapses by removing AMPA-type glutamate receptors (AMPARs). We show that synapses of CA1 pyramidal neurons become vulnerable to A{beta} when they express AMPAR subunit GluA3. We found that A{beta}-oligomers reduce the levels of GluA3 immobilized at spines, indicating they deplete GluA3-containing AMPARs from synapses. These A{beta}-driven effects critically depended on the PDZ-binding motif of GluA3. When GluA3 was expressed with a single amino acid mutation in its PDZ-binding motif that prevents GRIP binding, it did not end up at spines and A{beta} failed to trigger synaptic depression. GluA3 with a different point mutation in the PDZ-motif that leaves GRIP-binding intact but prevents its endocytosis, was present at spines in normal amounts but was fully resistant to effects of A{beta}. Our data indicate that A{beta}-mediated synaptic depression requires the removal of GluA3 from synapses. We propose that GRIP-detachment from GluA3 is a critical early step in the cascade of events through which A{beta} accumulation causes a loss of synapse.

neuroscience↗