Biology subjects

Vande Velde, C.

Publications and source records attributed to Vande Velde, C..

6 recordsLinked to original sources

bioRxiv2026

ZDHHC17 Links S-Acylation, Huntington Disease, VCP-associated Multisystem Proteinopathy, and Amyotrophic Lateral Sclerosis.

Protein mislocalization is an important contributor to neurodegeneration. We have identified disrupted S-acylation as a driver of mislocalization. S11acylation, the addition of long-chain fatty acids to cysteine residues, is mediated by the ZDHHC family of S-acyltransferases, and regulates protein localization by modulating protein hydrophobicity. Among these enzymes, we have identified ZDHHC17 as a central node in neurodegenerative disease. Although decreased ZDHHC17 activity is correlated with Huntington disease (HD) pathology, its broader contributions to neurodegeneration remain poorly defined. Here, we present new evidence that ZDHHC17 S-acylates or interacts with multiple proteins implicated in amyotrophic lateral sclerosis (ALS), including Valosin-containing protein (VCP) and TAR DNA Binding Protein (TDP1143). We further confirm that VCP, TDP-43, FUS, C9ORF72, and SQSTM1 are S-acylated across rodent models of multiple neurodegenerative diseases, including HD, VCP-associated multisystem proteinopathy, and ALS. Using biochemical S-acylation assays and confocal microscopy, we show that ZDHHC17 S-acylates VCP, depletes the nuclear localization of both VCP and TDP-43, and modulates VCP-dependent toxicity via ER-stress. We additionally demonstrate that TDP-43 is S-acylated by ZDHHC9. Motivated by these findings, we investigated the functional significance of motor-neuronal (MN) ZDHHC17 by studying dHip14 (the fly analog of ZDHHC17) in Drosophila melanogaster. Here, we found that motor neuron-specific dHip14 knockdown (KD) in flies resulted in impaired motor function, whereas ubiquitous depletion led to pharate-adult lethality. Together, these results highlight a shared mechanism across neurodegenerative diseases. Collectively, our findings position ZDHHC17 as a critical enzyme that links fatty acylation, protein homeostasis, and neurodegeneration. Understanding how ZDHHC17 orchestrates S-acylation across different cellular pathways may reveal new therapeutic strategies to restore proteostasis in neurodegenerative disease.

molecular biology↗

bioRxiv2026

TDP-43 pathology is linked to motor neuron loss but is independent of stress granules in vivo

Nuclear depletion and cytoplasmic aggregation of TDP-43 define a pathological signature across amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimers disease, and limbic-predominant age-related TDP-43 encephalopathy (LATE). Stress granule persistence and chronic activation of the integrated stress response (ISR) have been proposed to trigger this pathology, yet clinical trials targeting these pathways have failed despite robust target engagement suggesting that the prevailing model may be incomplete. Here, we use a physiologically relevant recurrent hyperthermia paradigm to directly test the relationship between stress granules and TDP-43 pathology in vivo. We find that RNA-binding proteins typically associated with stress granules persist as dynamic, phase-separated cytoplasmic assemblies in spinal motor neurons of both wild-type and mutant TDP-43 mice. These structures resolve spontaneously and are spatially distinct from TDP-43 puncta. Strikingly, in mutant TDP-43 mice with a compromised acute stress granule response, stress exposure provokes TDP-43 nuclear export and cytoplasmic deposition, culminating in selective loss of spinal -motor neurons after recurrent stress. Our results reveal that TDP-43 nuclear clearance and cytoplasmic aggregation can occur independently of stress granules in vivo, overturning a central assumption of TDP-43 pathogenesis. This paradigm shift reframes the mechanistic link between cellular stress and TDP-43 pathology, providing a new perspective for therapeutic strategies related to ISR modulation.

neuroscience↗

bioRxiv2024

Stress-induced mitochondrial fragmentation in endothelial cells disrupts blood-retinal barrier integrity causing neurodegeneration.

Increased vascular leakage and endothelial cell (EC) dysfunction are major features of neurodegenerative diseases. Here, we investigated the mechanisms leading to EC dysregulation and asked whether altered mitochondrial dynamics in ECs impinge on vascular barrier integrity and neurodegeneration. We show that ocular hypertension, a major risk factor to develop glaucoma, induced mitochondrial fragmentation in retinal capillary ECs accompanied by increased oxidative stress and ultrastructural defects. Analysis of EC mitochondrial components revealed overactivation of dynamin-related protein 1 (DRP1), a central regulator of mitochondrial fission, during glaucomatous damage. Pharmacological inhibition or EC-specific in vivo gene delivery of a dominant negative DRP1 mutant was sufficient to rescue mitochondrial volume, reduce vascular leakage, and increase expression of the tight junction claudin-5 (CLDN5). We further demonstrate that EC-targeted CLDN5 gene augmentation restored blood-retinal-barrier integrity, promoted neuronal survival, and improved light-evoked visual behaviors in glaucomatous mice. Our findings reveal that preserving mitochondrial homeostasis and EC function are valuable strategies to enhance neuroprotection and improve vision in glaucoma.

neuroscience↗

bioRxiv2021

Defining the Caprin-1 interactome in unstressed and stressed conditions

Cytoplasmic stress granules (SGs) are dynamic non-membranous foci containing translationally arrested mRNA and RNA binding proteins that form in response to a variety of cellular stressors. SGs may evolve into the cytoplasmic inclusions observed in many neurodegenerative diseases. Recent studies have examined the SG proteome by interrogating the interactome of G3BP1, a core SG protein. To gain further insight into the SG proteome, we employed an immunoprecipitation coupled with mass spectrometry approach of endogenous Caprin-1 in HeLa cells under unstressed or stressed conditions. Overall, we identified ~1,500 proteins that interact with Caprin-1. Interactors under stressed conditions were primarily annotated to the ribosome, spliceosome, and RNA transport pathways. We validated four Caprin-1 interactors that localized to arsenite-induced SGs: ANKHD1, Talin-1, GEMIN5, and SNRNP200. We also validated these stress-induced interactions in SH-SY5Y cells and determined that SNRNP200 also associated with osmotic and thermal induced SGs. Finally, we identified SNRNP200 in cytoplasmic aggregates in ALS spinal cord and motor cortex. Collectively, our findings provide the first description of the Caprin-1 protein interactome, identify novel cytoplasmic SG components, and reveal a SG protein in cytoplasmic aggregates in ALS patients. Proteomic data collected in this study are available via ProteomeXchange with identifier PXD023271.

cell biology↗

bioRxiv2020

TDP-43 stabilizes transcripts encoding stress granule protein G3BP1: potential relevance to ALS/FTD

TDP-43 nuclear depletion and concurrent cytoplasmic accumulation in vulnerable neurons is a hallmark feature of progressive neurodegenerative proteinopathies such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Cellular stress signalling and stress granule dynamics are now recognized to play a role in ALS/FTD pathogenesis. Defective stress granule assembly is associated with increased cellular vulnerability and death. G3BP1 (Ras-GAP SH3-domain-binding protein 1) is a critical stress granule assembly factor. Here, we define that TDP-43 stabilizes G3BP1 transcripts via direct binding of a highly conserved cis regulatory element within the 3UTR. Moreover, we show in vitro and in vivo that nuclear TDP-43 depletion is sufficient to reduce G3BP1 protein levels. Finally, we establish that G3BP1 transcripts are reduced in ALS/FTD patient neurons bearing TDP-43 cytoplasmic inclusions/nuclear depletion. Thus, our data suggest that, in ALS/FTD, there is a compromised stress granule response in disease-affected neurons due to impaired G3BP1 mRNA stability caused by TDP-43 nuclear depletion. These data implicate TDP-43 and G3BP1 loss of function as contributors to disease.

neuroscience↗

bioRxiv2019

The E3 ubiquitin ligase TRAF6 is a novel interacting protein of amyotrophic lateral sclerosis-linked misfolded SOD1

Amyotrophic lateral sclerosis (ALS) is a fatal disease, characterized by the selective loss of motor neurons leading to paralysis. Mutations in the gene encoding superoxide dismutase 1 (SOD1) are the second most common cause of familial ALS, and considerable evidence suggests that these mutations result in an increase in toxicity due to protein misfolding. We previously demonstrated in the SOD1G93A rat model that misfolded SOD1 exists as distinct conformers and forms deposits on mitochondrial subpopulations. Here, using SOD1G93A rats and conformation-restricted antibodies specific for misfolded SOD1 (B8H10 and AMF7-63), we identified the interactomes of the mitochondrial pools of misfolded SOD1. This strategy identified binding proteins that uniquely interacted with either AMF7-63 or B8H10-reactive SOD1 conformers as well as with a high proportion of interactors common to both conformers. Of this latter set, we identified the E3 ubiquitin ligase TNF receptor-associated factor 6 (TRAF6) as a SOD1 interactor and determined that exposure of the SOD1 functional loops facilitates this interaction. Of note, this conformational change was not universally fulfilled by all SOD1 variants and differentiated TRAF6-interacting from TRAF6 non-interacting SOD1 variants. Functionally, TRAF6 stimulated polyubiquitination and aggregation of the interacting SOD1 variants. TRAF6 E3 ubiquitin ligase activity was required for the former, but was dispensable for the latter, indicating that TRAF6-mediated polyubiquitination and aggregation of the SOD1 variants are independent events. We propose that the interaction between misfolded SOD1 and TRAF6 may be relevant to the etiology of ALS.

neuroscience↗