Biology subjects

Yuste-Checa, P.

Publications and source records attributed to Yuste-Checa, P..

5 recordsLinked to original sources

bioRxiv2026

Virus-mediated tau aggregate seeding in a cellular model

Formation of neuronal tau protein aggregates is a defining feature of tauopathies, including Alzheimers disease and frontotemporal dementia. Tau pathology propagates across brain regions by a cell-to-cell aggregate seeding mechanism. While epidemiological and experimental studies over the past three decades have implicated viral infections in aggregate-associated neurodegeneration, the underlying mechanisms remain unclear. Here, we show in a cell culture model that seeding competent tau aggregates are efficiently packaged into lentiviral particles and induce tau aggregation in recipient cells in a virus receptor-dependent manner. Tau aggregates interact with the viral Gag polyprotein, likely facilitating their incorporation into virions. Virus-dependent tau seeding requires protease-mediated maturation of the envelope protein to enable efficient fusion of the viral envelope with the plasma membrane of the recipient cell. Thus, tau aggregate packaging is compatible with the formation of mature, infectious virions. These findings are consistent with a possible role of viral infection in neurodegenerative disease progression and offer a robust, versatile platform to model tau propagation in cellular systems and animal models.

Cell Biology↗

bioRxiv2025

Mitochondrial proteostatic stress disrupts mitoribosome biogenesis and translation

Protein aggregation in various cellular compartments is a hallmark of proteostasis impairment linked to aging and numerous pathologies. Mitochondrial function depends on a balanced interplay of proteins imported from the cytosol as well as those synthesized on mitochondrial ribosomes (mitoribosomes). Here, we reveal an unexpected susceptibility of mitoribosome biogenesis to organellar proteostatic stress. Importing aggregation-prone proteins into yeast and human mitochondria triggered a chain of detrimental events involving extensive co-aggregation of newly-imported mitoribosome subunits and other RNA-binding proteins, as well as local disruption of mitochondrial cristae morphology. As a result, mitoribosome assembly and mitochondrial translation were severely impaired, leading to respiratory deficiency and, ultimately, loss of mitochondrial DNA. Surprisingly, dysfunction of mitochondrial HSP60 phenocopied the ribosome biogenesis defect and inhibition of translation, indicating a pronounced chaperone dependence of mitoribosome proteins. Declining mitochondrial translation likely contributes to aging and diseases associated with deficiencies in mitochondrial protein quality control machinery.

cell biology↗

bioRxiv2024

Hydrophobic tails enable diverse functions of the extracellular chaperone clusterin

Clusterin, a conserved secretory glycoprotein abundant in blood plasma and cerebrospinal fluid, functions as a molecular chaperone and apolipoprotein (Wyatt et al. 2013, Raulin et al. 2022). Dysregulation of clusterin is linked to late-onset Alzheimers disease, cardiovascular pathology and cancer (Rohne et al. 2016, Satapathy and Wilson 2021, Wilson et al. 2023). Despite its prominent role in extracellular proteostasis, the chaperone mechanism of clusterin has remained unclear. Here we present crystal structures of human clusterin, revealing a discontinuous three-domain architecture. Structure-based mutational analysis demonstrated that two intrinsically disordered, hydrophobic peptide tails enable diverse clusterin activities. Resembling the N-terminal substrate binding regions of so-called small heat shock proteins, these sequences mediate clusterins chaperone function in suppressing amyloid-{beta}, tau and -synuclein aggregation. In conjunction with highly conserved surface areas, the tail segments also participate in clusterin binding to very low density lipoprotein receptor (VLDLR) and cellular uptake. Moreover, the disordered tails cooperate with an adjacent amphipathic helix in lipoprotein formation, but remain accessible for chaperone function in the lipoprotein complex. The remarkable versatility of these sequences allows clusterin to function alone or bound to lipid in maintaining solubility of aberrant extracellular proteins and facilitating their clearance by endocytosis and lysosomal degradation.

molecular biology↗

bioRxiv2022

The AAA+ chaperone VCP disaggregates Tau fibrils and generates aggregate seeds

Amyloid-like aggregates of the microtubule-associated protein Tau are associated with several neurodegenerative disorders including Alzheimers disease. The existence of cellular machinery for the removal of such aggregates has remained unclear, as specialized disaggregase chaperones are thought to be absent in mammalian cells. Here we show in cell culture and in neurons that the AAA+ chaperone VCP is recruited to ubiquitylated Tau fibrils, resulting in their efficient disaggregation. Aggregate clearance depends on the functional cooperation of VCP with Hsp70 and the ubiquitin-proteasome machinery. Inhibition of VCP activity stabilizes large Tau aggregates, and is accompanied by a reduction in the amount of Tau species competent of prion- like aggregate seeding in recipient cells. Thus, disaggregation by VCP generates seeding-active Tau as byproduct. These findings identify VCP as a core component of the machinery for the removal of neurodegenerative disease aggregates and suggest that its activity can be associated with enhanced aggregate spreading in tauopathies.

cell biology↗

bioRxiv2021

The extracellular chaperone Clusterin enhances Tau aggregate seeding in a cellular model

Spreading of aggregate pathology across brain regions acts as a driver of disease progression in Tau-related neurodegeneration, including Alzheimers disease (AD) and frontotemporal dementia. Aggregate seeds released from affected cells are internalized by naive cells and induce the prion-like templating of soluble Tau into neurotoxic aggregates. Here we show in a cellular model system and in neurons that Clusterin, an abundant extracellular chaperone, strongly enhances Tau aggregate seeding. Upon interaction with Tau aggregates, Clusterin stabilizes highly potent, soluble seed species. Tau/Clusterin complexes enter recipient cells via endocytosis and compromise the endolysosomal compartment, allowing transfer to the cytosol where they propagate aggregation of endogenous Tau. Thus, upregulation of Clusterin, as observed in AD patients, may enhance Tau seeding and possibly accelerate the spreading of Tau pathology.

cell biology↗