Biology subjects

Riera-Tur, I.

Publications and source records attributed to Riera-Tur, I..

3 recordsLinked to original sources

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↗

bioRxiv2020

In situ architecture of neuronal alpha-Synuclein inclusions

-Synuclein (-Syn) aggregation is a hallmark of devastating neurodegenerative disorders including Parkinsons disease (PD) and multiple systems atrophy (MSA)1,2. -Syn aggregates spread throughout the brain during disease progression2, suggesting mechanisms of intercellular seeding. Formation of -Syn amyloid fibrils is observed in vitro3,4 and fibrillar -Syn has been purified from patient brains5,6, but recent reports questioned whether disease-relevant -Syn aggregates are fibrillar in structure7-9. Here we use cryo-electron tomography (cryo-ET) to image neuronal Lewy body-like -Syn inclusions in situ at molecular resolution. We show that the inclusions consist of -Syn fibrils crisscrossing a variety of cellular organelles such as the endoplasmic reticulum (ER), mitochondria and autophagic structures, without interacting with membranes directly. Neuronal inclusions seeded by recombinant or MSA patient-derived -Syn aggregates have overall similar architecture, although MSA-seeded fibrils show higher structural flexibility. Using gold-labeled seeds we find that aggregate nucleation is predominantly mediated by -Syn oligomers, with fibrils growing unidirectionally from the seed. Our results conclusively demonstrate that neuronal -Syn inclusions contain -Syn fibrils intermixed with cellular membranes, and illuminate the mechanism of aggregate nucleation.

cell biology↗

bioRxiv2019

Amyloid-like aggregates cause lysosomal defects in neurons via gain-of-function toxicity

The autophagy-lysosomal pathway is impaired in many neurodegenerative diseases characterized by protein aggregation, but the link between aggregation and lysosomal dysfunction remains poorly understood. Here, we combine cryo-electron tomography, proteomics and cell biology studies to investigate the effects of protein aggregates in primary neurons. We use artificial amyloid-like {beta}-sheet proteins ({beta} proteins) to focus on the gain-of-function aspect of aggregation. These proteins form fibrillar aggregates and cause neurotoxicity. We show that late stages of autophagy are impaired by the aggregates, resulting in lysosomal alterations reminiscent of lysosomal storage disorders. Mechanistically, {beta} proteins interact with and sequester AP-31, a subunit of the AP-3 adaptor complex involved in protein trafficking to lysosomal organelles. This leads to destabilization of the AP-3 complex, missorting of AP-3 cargo, and lysosomal defects. Restoring AP-31 expression ameliorates neurotoxicity caused by {beta} proteins. Altogether, our results highlight the link between protein aggregation and neurotoxicity, pointing to lysosomes as particularly vulnerable organelles.

cell biology↗