Biology subjects

BUEE, L.

Publications and source records attributed to BUEE, L..

3 recordsLinked to original sources

bioRxiv2026

APP metabolism is regulated by p97/VCP through an autophagy and endolysosome-dependent mechanism

Deregulation of amyloid precursor protein (APP) metabolism leads to the production of pathological proteoforms of A{beta} peptides, which ultimately form amyloid deposits, a primary pathological feature of Alzheimers disease (AD). The accumulation of misfolded proteins and alterations in protein degradation systems, such as the ubiquitin-proteasome system, endoplasmic reticulum-associated degradation, and autophagy-lysosomal pathways, also contribute to AD development. The Valosin-Containing Protein AAA-ATPase (p97/VCP) is a crucial regulator of proteostasis, facilitating the clearance of misfolded proteins by the proteasome and other protein degradation systems. Here, we investigated whether VCP influences APP processing. Reducing VCP expression or inhibiting its ATPase activity led to the accumulation of mature, full-length APP in cells, thereby decreasing APP trafficking to the cell surface. Downstream of APP-CTFs secretase processing, p97/VCP modulates APP-CTFs cleavage and degradation via autophagy and endolysosomal-dependent mechanisms. Our findings demonstrate that VCP is involved in APP metabolism at two levels: controlling APP trafficking within the cell secretory pathway and regulating autophagy-dependent degradation of APP-CTFs, suggesting a potential role for VCP in the APP deregulation observed in AD.

cell biology↗

bioRxiv2025

Platelet concentrate-derived extracellular vesicles promote adult hippocampal neurogenesis

Platelet-derived materials are emerging as promising, cell-free biotherapies for regenerative medicine. While platelet lysates have shown neuroprotective activity in preclinical models, the neurogenic potential of platelet concentrate-derived extracellular vesicles (pEVs) remains underexplored. Here, we evaluated the effects of human pEVs and a neuroprotective heat-treated human platelet lysate (HPPL) on adult hippocampal neurogenesis using both an ex vivo neurosphere assay and an in vivo intranasal administration model. pEVs selectively enhanced dentate gyrus (DG)-derived neurosphere growth, even in the absence of exogenous growth factors, and were internalized by neural precursors. In vivo, short-term pEV delivery increased EdU proliferating cells in the DG, while long-term administration (28 days) elevated the proportion of newborn mature neurons. By contrast, HPPL primarily promoted early neurogenesis by expanding immature DCX neurons. Quantitative proteomics of DG tissue after pEV treatment revealed 111 differentially expressed proteins, with enrichment in pathways related to oxidative phosphorylation, Notch4 signaling, myelination, and MHC class I-mediated antigen presentation. Downregulated proteins included cytoskeletal and translation-related regulators, suggesting a shift toward neuronal differentiation and circuit integration. Biophysical characterization confirmed the purity and vesicular nature of pEVs, with a defined protein cargo including immune modulators and ECM-interacting molecules such as CD44, lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1), and complement proteins. These findings identify allogeneic pEVs as multifunctional agents that modulate neural precursor cell fate and brain tissue remodeling through coordinated metabolic and immunoregulatory mechanisms. This work supports the translational potential of pEV-based therapeutics for promoting hippocampal neurogenesis and cognitive repair in neurodegenerative and age-related brain disorders.

neuroscience↗

bioRxiv2021

Functional analyses of two novel LRRK2 pathogenic variants in familial Parkinson's disease

BackgroundPathogenic variants in the LRRK2 gene are a common monogenic cause of Parkinsons disease. However, only seven variants have been confirmed to be pathogenic. ObjectivesWe identified two novel LRRK2 variants (H230R and A1440P) and performed functional testing. MethodsWe transiently expressed wildtype, the two new variants, or two known pathogenic mutants (G2019S and R1441G), in HEK-293T cells, with or without LRRK2 kinase inhibitor treatment. We characterized the phosphorylation and kinase activity of the mutants by western blotting. Thermal shift assays were performed to determine the folding and stability of the LRRK2 proteins. ResultsThe two variants were found in two large families and segregate with the disease. They display altered LRRK2 phosphorylation and kinase activity. ConclusionsWe identified two novel LRRK2 variants which segregate with the disease. The results of functional testing lead us to propose these two variants as novel causative mutations for familial Parkinsons disease.

genetics↗