Biology subjects

Jacquemyn, J.

Publications and source records attributed to Jacquemyn, J..

3 recordsLinked to original sources

bioRxiv2025

Glucosylceramide induced ectosomes propagate pathogenic α-synuclein in Parkinson's disease

Intercellular transmission of -synuclein contributes to Parkinsons disease pathology. Yet, the mechanisms of -synuclein spread are not fully understood. Here, we used live-cell microscopy to examine the impact of Parkinsons disease associated lipid alterations on -synuclein release. We discovered that increased glucosylceramides induce ectosome shedding from primary neurons, and from dopaminergic neurons derived from Parkinsons disease patient iPSCs harboring mutations in GBA1 (N370S, L444P and W378G) and LRRK2 (G2019S and R1441H) compared to their isogenic control. We show that elevated glucosylceramide similarly increases vesicle release and uptake by other neurons in living mouse brains using 2-photon microscopy. Finally, we show that ectosomes are loaded with pathogenic -synuclein and lead to the transmission of -synuclein pathology to neighbouring neurons. These data reveal ectosomes as the predominant route for -synuclein transmission that can only be appreciated by live-cell imaging technologies.

cell biology↗

bioRxiv2022

Parkinson mutations in DNAJC6 cause lipid defects and neurodegeneration that are rescued by Synj1

Recent evidence links dysfunctional lipid metabolism to the pathogenesis of Parkinsons disease, but the mechanisms are not resolved. Here, we created a new Drosophila knock-in model of DNAJC6/Auxilin and find that the pathogenic mutation causes synaptic dysfunction, neurological defects and neurodegeneration, as well as specific lipid metabolism alterations. In these mutants membrane lipids containing long-chain polyunsaturated fatty acids, including phosphatidylinositol lipid species that are key for synaptic vesicle recycling and organelle function are reduced. Overexpression of another protein mutated in Parkinsons disease, Synaptojanin-1, known to bind and synthesize specific phosphoinositides, strongly rescues the DNAJC6/Auxilin neuronal defects and neurodegeneration. Our work reveals a functional relation between two proteins mutated in Parkinsons disease and implicates deregulated phosphoinositide metabolism in the maintenance of neuronal integrity and neuronal survival in Parkinsonism.

cell biology↗

bioRxiv2020

The Torsin/ NEP1R1-CTDNEP1/ Lipin axis regulates nuclear envelope lipid metabolism for nuclear pore complex insertion

Torsin ATPases of the endoplasmic reticulum (ER) and nuclear envelope (NE) lumen inhibit Lipin-mediated phosphatidate (PA) to diacylglycerol (DAG) conversion by an unknown mechanism. This excess PA metabolism is implicated in TOR1A/TorsinA diseases, but it is unclear whether it explains why Torsin concomitantly affects nuclear structure, lipid droplets (LD), organelle and cell growth. Here a fly miniscreen identified that Torsins affect these events via the NEP1R1-CTDNEP1 phosphatase complex. Further, Torsin homo-oligomerization rather than ATPase activity was key to function. NEP1R1-CTDNEP1 activates Lipin by dephosphorylation. We show that Torsin prevents CTDNEP1 from accumulating in the NE and excludes Lipin from the nucleus. Moreover, this repression of nuclear PA metabolism is required for interphase nuclear pore biogenesis. We conclude that Torsin is an upstream regulator of the NEP1R1-CTDNEP1/ Lipin pathway. This connects the ER/NE lumen with PA metabolism, and affects numerous cellular events including it has a previously unrecognized role in nuclear pore biogenesis.HighlightsNuclear envelope PA-DAG-TAG synthesis is independently regulated by Torsin and Torip/LAP1Torsin removes CTDNEP1 from the nuclear envelope and excludes Lipin from the nucleusExcess nuclear envelope NEP1R1-CTDNEP1/ Lipin activity impairs multiple aspects of NPC biogenesisNEP1R1-CTDNEP1/ Lipin inhibition prevents cellular defects associated with TOR1A and TOR1AIP1 / LAP1 diseaseCompeting Interest StatementThe authors have declared no competing interest.View Full Text

cell biology↗