Biology subjects

Louros, N.

Publications and source records attributed to Louros, N..

4 recordsLinked to original sources

bioRxiv2022

Tau amyloid polymorphism is shaped by local structural propensities of its protein sequence

Different tauopathies are characterized by specific amyloid filament folds that are conserved between patients. Disease-specific tau filament folds probably reflect the specific pathological contexts leading to their formation including isoforms or post-translational modifications. Little is known, however, as to whether and how intrinsic conformational tendencies of the tau sequence itself contribute to its polymorphism. Using cryo-EM structure determination we find that a short amyloidogenic C-terminal peptide consisting of residues 350-362 of the tau repeat domain adopts the same polymorphic conformations in isolation as it does in the context of major disease-associated protofilament folds. Biophysical characterisation and molecular modelling show that the amyloid conformations adopted by this peptide constitute core structural motifs stabilizing distinct disease-associated tau filament folds. In accordance this segment also contributes to the efficient propagation of human AD tau seeds in tau reporter cells while it is irrelevant to heparin-induced recombinant seeds. Our findings suggest that tau 350-362 is key to the propagation of disease-associated tau polymorphs and that the conformational preferences of this segment predispose to the topological diversity observed in tau filament folds.

biophysics↗

bioRxiv2022

EndophilinA-dependent coupling between activity-dependent calcium influx and synaptic autophagy is disrupted by a Parkinson-risk mutation

Neuronal activity and neurotransmitter release cause use-dependent decline in protein function. However, it is unclear how this is coupled to local protein turnover and quality control mechanisms. Here we show that the endocytic protein Endophilin-A (EndoA/ENDOA1) couples activity-induced calcium influx to synaptic autophagy and neuronal survival. We identify single mutations in the EndoA flexible region that either increases EndoA diffusion and promotes autophagosome formation in the absence of calcium, or immobilizes EndoA and blocks autophagy, even in the presence of calcium. Hence, the EndoA flexible region is a switch that responds to calcium, regulating EndoA nanoscale synaptic organization and association with autophagosomes driving their formation. Interestingly, a pathogenic variant in the human ENDOA1 variable region that confers risk to Parkinsons disease (PD), also confines ENDOA1 to the synaptic plasma membrane and equally blocks autophagy in flies in vivo and in induced human neurons. Thus, our work reveals a mechanism neurons use to connect neuronal activity to local protein turnover by autophagy, which is critical for neuronal survival.

neuroscience↗

bioRxiv2021

Heterotypic Aβ interactions facilitate amyloid assembly and modify amyloid structure

It is still unclear why pathological amyloid deposition initiates in specific brain regions, nor why specific cells or tissues are more susceptible than others. Amyloid deposition is determined by the self-assembly of short protein segments called aggregation-prone regions (APRs) that favour cross-{beta} structure. Here we investigated whether A{beta} amyloid assembly can be modified by heterotypic interactions between A{beta} APRs and short homologous segments in otherwise unrelated human proteins. We identified heterotypic interactions that accelerate A{beta} assembly, modify fibril morphology and affect its pattern of deposition in vitro. Moreover, we found that co-expression of these proteins in an A{beta} reporter cell line promotes A{beta} amyloid aggregation. Importantly, reanalysis of proteomics data of A{beta} plaques from AD patients revealed an enrichment in proteins that share homologous sequences to the A{beta} APRs, suggesting heterotypic amyloid interactions may occur in patients. Strikingly, we did not find such a bias in plaques from overexpression models in mouse. Based on these data, we propose that heterotypic APR interactions may play a hitherto unrealised role in amyloid-deposition diseases.

neuroscience↗

bioRxiv2021

A structural analysis of amyloid polymorphism in disease: clues for selective vulnerability?

The increasing amount of amyloid structures offers an opportunity to investigate the general principles determining amyloid stability and polymorphism in disease. We find that amyloid stability is dominated by about 30% of residues localized in few segments interspersed with regions that are often structurally frustrated in the cross-{beta} conformation. These stable segments correspond to known aggregation-nucleating regions and constitute a cross-{beta} structural framework that is shared among polymorphs. Alternative tertiary packing of these segments within the protofibril results in conformationally different but energetically similar polymorphs. This combination of a conserved structural framework along the axis and energetic ambiguity across the axis results in polymorphic plasticity that explains a number of fundamental amyloid properties, including fibril defects and brittleness but also the polymorphic instability of amyloids in simple aqueous buffers. Together these findings suggest a structural model for in vivo polymorphic bias and selective cellular vulnerability whereby (1) polymorphic bias is induced by particular templating interactions in susceptible cells, (2) once formed specific polymorphs are entropically primed to selectively bind similar targets in neighbouring cells, (3) conservation of polymorphic bias during pathological spreading implies the continued presence of similar templating interactions in successive susceptible cells and (4) absence of templating interactions relaxes polymorphic bias possibly allowing for the modification of cellular susceptibilities during disease progression by novel templating interactions.

neuroscience↗