Biology subjects

Rezaei, H.

Publications and source records attributed to Rezaei, H..

15 recordsLinked to original sources

bioRxiv2026

Unfolding of the disease-linked bank vole prion protein E200K in the context of PrPSc propagation

The elucidation of the atomistic structure of PrPSc has, disappointingly, not revealed the mechanism underlying prion propagation. This is because PrPSc has been shown to be a standard amyloid, and as such, it can only template a polypeptide chain that is unfolded. Therefore, while PrPSc can easily template the disordered ~90-120 domain of an incoming PrPC molecule, it does not have any obvious capacity to template its ~121-231 folded domain (FD). The FD needs to accommodate into the ~121-230 PrPSc surface, an inert "Procrustean bed". We have recently proposed that unfolding of the FD is a prerequisite for its conversion to the PrPSc conformation and using experimental and computational methods identified the likely early events of such process using bank vole (BV)PrP(90-231) as our working model. We concluded that a key early event is the destabilization of the short {beta}1-{beta}2 assembly, and that the segment contiguous to the disordered tail, ~121-140, encompassing {beta}1 and its adjacent coils, is the most likely region to unfold first. In the present study we applied the same methodology to the disease-related PrP mutant E200K. E200K is the most prevalent mutation leading to familial prion disease in humans, yet the stability of its FD is only marginally lower compared to that of the protein with the wild type (wt) sequence. We, therefore, aimed at assessing whether the early unfolding events of BVPrPC(E200K) are similar or different to those of wtBVPrPC and whether such early unfolding route might provide insight into the extreme capacity of PrPC(E200K) to spontaneously generate PrPSc. It should be noted that generation and propagation of PrPSc are distinct phenomena, even though both are mechanistically related and dependent on conformational changes in PrPC. Our data show that early unfolding events of BVPrPC(E200K) are essentially similar to those of wt BVPrPC. However, interesting nuances exist.

biochemistry↗

bioRxiv2026

Non-fibrillar prion protein oligomers transmit structural information during early assembly

The prion paradigm is founded on the transmission of structural information from aggregated assemblies to soluble protein substrates, a process classically attributed to fibril-end-mediated templating. Whether non-fibrillar assemblies or transient oligomeric states can also participate in folding information transfer remains unclear. Here, using recombinant prion protein (PrP), rational mutagenesis, hetero-oligomerization assays, arrested reaction conditions, and single-particle atomic force microscopy coupled to infrared nano-spectroscopy (AFM-IR), we examine the earliest stages of PrP assembly from the perspective of folding information transmission. We show that polymerization-defective PrP variants can be incorporated into oligomeric assemblies through structural complementation, in which folding information supplied by wild-type PrP restores their assembly competence. Under arrested reaction conditions, transient polymerization-competent conformers further contribute to folding information transfer at subcritical concentrations. Domain-resolved analyses reveal a modular oligomeric architecture in which a {beta}-sheet-rich B domain constitutes the primary scaffold for folding information transfer. Preformed O1 oligomers then act as autonomous conformational templates that promote mutant incorporation and undergo hierarchical condensation through accretion of a structurally distinct E domain. Together, these findings demonstrate that non-fibrillar PrP oligomers and transient assembly intermediates can store and transmit folding information and may function as oligomer-based secondary nucleation platforms, expanding the conceptual framework of prion assembly beyond fibril-end elongation alone.

biochemistry↗

bioRxiv2025

Over-Reliance on Prior Expectations in Relapsing-Remitting Multiple Sclerosis

Cognitive impairment is a common and disabling feature of multiple sclerosis (MS). Bayesian models of perception and action provide a powerful framework to better understand how cognitive processes are altered in MS. In this case-control study, we employed a time reproduction paradigm within a Bayesian framework to investigate the underlying mechanisms of cognitive dysfunction in patients with relapsing-remitting MS. We applied a modified Bayesian observer model, which partitions time reproduction into three stages: sensory measurement, time estimation, and motor response. We found that both MS and control groups showed a systematic bias in reproducing time, overestimating short intervals and underestimating long intervals. This bias was significantly larger in patients with MS compared with controls, reflecting an over-reliance on prior expectations relative to sensory-motor information. Computational modeling indicated that this increased bias in the MS group was driven by greater measurement noise during the sensory stage. Moreover, central tendency bias increases with age in healthy participants as reliance on prior expectations becomes stronger than sensory-motor evidence. Interestingly, we found that this age-related effect on bias was absent in patients with MS. Further analysis showed both younger and older patients performed equally biased, and their performance was similar to older healthy participants.

neuroscience↗

bioRxiv2025

Delay selection by spike-timing-dependent plasticity shapes efficient networks for signal transmission

Information processing in the brain relies on efficient communication between different brain regions. Brain oscillations can control signal transmission in brain networks by modulating the timing and excitability of sender and receiver areas. For effective transmission, signals should arrive at target areas when their excitability is maximized. For reciprocally connected neural populations, this mechanism works if the transmission delay matches the period of their evoked oscillation. However, the mechanisms underlying such development of the connections with matched delays remain elusive. While transmission delays in brain networks change during development, the process by which delays are tuned for efficient transmission is unknown. Here, we demonstrate that the well-known Hebbian learning rule can provide a mechanism for selecting connections with delays that match the period of network oscillations. We consider a reciprocally connected bi-layer network of excitatory and inhibitory neurons that generate network-level oscillations spontaneously or in response to external stimuli. When exposed to spiketiming-dependent plasticity (STDP), the network self-organizes to potentiate connections with delays matching the oscillation period, while depressing those with non-matching delays. Our findings shed light on how transmission delays may evolve during learning and development to optimize the organization of brain networks for efficient signal transmission.

neuroscience↗

bioRxiv2025

Unfold to refold: Tracking the initial steps of PrPC unfolding in the context of PrPSc propagation

It might have been believed that elucidation of the atomistic structure of PrPSc would lead to an immediate understanding of the mechanism of prion propagation. However, PrPSc, now known to be a "simple" amyloid, can just template a previously unfolded polypeptide chain. Therefore, PrPSc can easily template the disordered [~]90-120 domain of an incoming PrPC molecule, but not its [~]121-231 folded domain (FD). The FD needs to accommodate into the [~]121-230 PrPSc surface, an inert "procrustean bed". Thus, a mechanism for concerted unfolding/refolding of the FD must exist, with FD unfolding as a key element. To explore how this might happen, we performed thermal unfolding of recombinant bank vole PrPC(90-231), that is a universal PrPSc propagator PrPSc, tracking changes at the residue level with solution NMR to pinpoint early unfolding propensity. Our data suggest that a key early event is the destabilization of the short {beta}1-{beta}2 assembly, and that the segment contiguous to the disordered tail, [~]121-140, encompassing {beta}1 and its adjacent coils, is the most likely region to unfold first. Spectroscopic data obtained at higher temperatures suggest that portions of alpha helix 2 are likely the last elements of the FD to unfold and refold into the PrPSc conformation. Molecular Dynamics simulations assisted the interpretation of these changes and suggest separation of 1 from the rest of the FD ensemble. Our data provide a conceivable timeline of the early events in PrPSc-assisted conversion of PrPC and should serve as a starting framework to develop a future atomistic model of PrPSc propagation.

biochemistry↗

bioRxiv2024

Human PrP E219K as a new and promising substrate for RT-QuIC amplification of human prion strains: a first step towards strain discrimination

Prion diseases are fatal neurodegenerative diseases that affect mammals through the transconformation of a host protein, the prion protein (PrP), into a toxic and pathogenic conformer termed PrPSc. Until now, the diagnosis is only confirmed with a post-mortem histology study of the central nervous system. Among the methods to detect the etiological agent, in vitro amplification techniques have emerged as very sensitive, highly specific and rapid tools, even though some prion strains remain refractory or difficult to amplify. Here we report the use of a new recombinant substrate for Real-Time Quaking Induced Conversion (RT-QuIC), a natural polymorphism of human prion protein with a lysine at position 219 instead of a glutamic acid, PrP E219K. This substrate amplifies the six sporadic human strains responsible for Creutzfeldt-Jakob Disease (CJD) and the strain responsible for its variant form in a few hours and over a large dilution range of the seeds. Moreover, based on the lag time of the amplification reactions, the PrP E219K substrate allows to discriminate between sporadic and variant CJD strains, a first step towards an ante-mortem typing of the prion strain affecting a patient.

pathology↗

bioRxiv2024

The dynamics of prion spreading is governed by the interplay between the non-linearities of tissue response and replication kinetics

Prion diseases, or Transmissible Spongiform Encephalopathies (TSE), are neurodegenerative disorders caused by the accumulation of misfolded conformers (PrPSc) of the cellular prion protein (PrPC). During the pathogenesis, the PrPSc seeds disseminate in the central nervous system and convert PrPC leading to the formation of insoluble assemblies. As for conventional infectious diseases, variations in the clinical manifestation define a specific prion strain which correspond to different PrPSc structures. In this work, we implemented the recent developments on PrPSc structural diversity and tissue response to prion replication into a stochastic reaction-diffusion model using an application of the Gillespie Algorithm. We showed that this combination of non-linearities can lead prion propagation to behave as a complex system, providing an alternative to the current paradigm to explain strain specific phenotypes, tissue tropisms and strain co-propagation while also clarifying the role of the connectome in the neuro-invasion process.

neuroscience↗

bioRxiv2023

The smallest infectious substructure encoding the prion strain structural determinant revealed by spontaneous dissociation of misfolded prion protein assemblies

It is commonly accepted that the prion replicative propensity and strain structural determinant (SSD) are encoded in the fold of PrPSc amyloid fibril assemblies. By exploring the quaternary structure dynamicity of several prion strains, we revealed that all mammalian prion assemblies exhibit the generic property of spontaneously generating two sets of discreet infectious tetrameric and dimeric species differing significantly by their specific infectivity. By using perturbation approaches such as dilution and ionic strength variation, we demonstrated that these two oligomeric species were highly dynamic and evolved differently in the presence of chaotropic agents. In general, our observations of seven different prion strains from three distinct species highlight the high dynamicity of PrPSc assemblies as a common and intrinsic property of mammalian prions. The existence of such small infectious PrPSc species harboring the SSD indicates that the prion infectivity and the SSD are not restricted only to the amyloid fold but can also be encoded in other alternative quaternary structures. Such diversity in the quaternary structure of prion assemblies tends to indicate that the structure of PrPSc can be divided into two independent folding domains: a domain encoding the strain structural determinant and a second domain whose fold determines the type of quaternary structure that could adopt PrPSc assemblies. HighlightsO_LIMammalian prion assemblies are highly dynamic C_LIO_LIPrion assemblies spontaneously disassemble into two infectious oligomers C_LIO_LIPrion infectivity is not exclusively encoded in the amyloid fibrils structure C_LIO_LITwo independent folding domains could structure Prion assemblies C_LI

biochemistry↗

bioRxiv2023

Pathogenicity, strain properties and interspecies transmission capacity of pure recombinant prion protein assemblies

The pathogenicity of fibrillar assemblies derived from bacterially expressed recombinant prion protein (rPrP) has been key to the demonstration that prions are infectious proteins responsible for human and animal transmissible spongiform encephalopathies. Yet, their use in identifying which structural PrP features are important for prion biology, including strain properties and capacity to transmit between species, has been hampered by their limited transmissibility de novo. We report the generation of prions with distinct biological characteristics from rPrP assemblies differing only in their primary structure (hamster, mouse and human amino acid sequence). These rPrP assemblies were transmissible to transgenic mice expressing hamster PrP, causing a clinical disease at full attack rate, brain deposition of pathological prion protein PrPSc and spongiform degeneration. Their adaptation process on serial sub-passaging seemed to depend, as for genuine prions, on the presence of a species/transmission barrier, due notably to PrP sequence mismatch. Remarkably, one of the strains obtained is an unprecedented shortened prion, lacking the 90-140 amino-acid region which is believed to be key to infectivity and structural stability of disease-associated PrP assemblies. Finally, we provide evidence that rPrP prionogenicity lies in the structural organization and/or heterogeneity of the rPrP assemblies. These preparations of rPrP offer unprecedented opportunities for meaningful studies correlating the dynamicity and structures of PrPSc assemblies to prion pathobiology. Author summaryPrions are infectious proteins, causing rapidly progressive neurodegenerative diseases in animals and humans. They are formed from the assisted-refolding and aggregation of the host-encoded prion protein (PrP). During the propagation of the disease, pathological PrP forces normal PrP to adopt its own conformation by a self-templating process. In infected host, different pathological structures of PrP or strains are found, causing diseases with specific biological phenotypes. Prions can also transmit between species. This capacity is limited by a species barrier, which critically depends on the infecting strain and PrP primary structure. How strain biological information is encoded in PrP structural fold remains unknown. We describe here the generation of different bona fide prion strains with markedly distinct adaptation capacities by transmission of refolded assemblies derived from bacterially-derived recombinant PrP (rPrP) of different species. We provide evidence that pathogenicity lies in the structural organization and/or heterogeneity of rPrP assemblies. Pathological PrP from one of the generated strains exhibited unique molecular features, including absence of domains that are thought to be key to prion infectivity, according to most recent ultrastructural studies. Our findings provide new insights for generating prion infectious material and resolving mechanisms of infectivity acquisition during PrP conversion process.

microbiology↗

bioRxiv2021

Solid state NMR reveals a parallel in register architecture for an infectious recombinant prion

Two alternative architectures have been proposed for PrPSc, the most notorious prion: a parallel in register {beta} stack (PIRIBS) and a 4-rung {beta}-solenoid (4R{beta}S). We challenged these two models by measuring intermolecular 13C-13C dipole-dipole couplings of 13CO-labelled Phe residues in a fully infectious sample of recombinant bank vole PrPSc (recBVPrPSc) using a PITHIRDS-CT solid state NMR (ssNMR) experiment. To our surprise, data strongly support a PIRIBS architecture. However, the mean distance measured ([~]6.5 [A]) suggests that a minimum of two of the three Phe residues are not perfectly stacked at the canonical [~]5 [A] cross-{beta} distance. Additional ssNMR experiments show some local conformational variability of the Phe residues within limits of a relatively high rigidity. The most parsimonious interpretation of our data is that recBVPrPSc is arranged as a PIRIBS, although additional conformers with alternative architectures cannot be excluded, including a mixture of PIRIBS and 4R{beta}S. Author summaryPrPSc is the most notorious prion. It is an infectious protein that cuases fatal neurodegenerative diseases in humans and animals. PrPSc is the aberrant version of a brain protein, PrPC. PrPSc and PrPC have the same prinary structure, but different secondary, tertiaty and quaternary structures. PrPSc is capable of templating PrPC to convert to the PrPSc conformation, which is the basis of its capacity to propagate. Two plausible structural models of PrPSc have been proposed, the four-rung {beta}-solenoid (4R{beta}S) and the parallel in-register {beta} stack (PIRIBS) model. In both cases the driving force of the templating mechanism consists of "sticky" surface {beta}-strands; however, in the PIRIBS model all the {beta}-strands that conform a PrPSc monomer lie flat on a surface whereas in the 4R{beta}S model they wind in a corkscrew fashion. Here, we analyzed fully infectious recombinant PrPSc using a solid state NMR technique, PITHIRDS, that allows probing distances between specific labelled amino acid residues. To our surprise (as we have defended the 4R{beta}S model in the past), results clearly show the presence of a PIRIBS structure in our sample.

biochemistry↗

bioRxiv2020

An alternative model to prion fragmentation based on the detailed balance between PrPSc and suPrP

Prion assemblies responsible for transmissible spongiform encephalopathies grow in the form of linear amyloid fibrils. Traditional models for prion growth and tissue-spreading have relied upon the assumption that propagation is based on the process of fragmentation, wherein an assembly literally breaks in two, creating additional templating interfaces. Recent experimental data shows that PrPSc assemblies are in detailed balance with an elementary oligomeric building block called suPrP. In the present work we compare the dynamics of the canonical model of induced-fragmentation to the model of PrPSc assemblies in detailed balance with suPrP. The model is a dynamical system describing the populations of fibrils of varying lengths as a function of time; we analyze the system via both analytical and numerical techniques. We demonstrate that the detailed balance between suPrP and PrPSc model can equivalently replace the induced-fragmentation model. This equivalence opens a new opportunity in an optimal control problem.

neuroscience↗

bioRxiv2019

Host prion protein expression levels impact prion tropism for the spleen

Prions are pathogens formed from abnormal conformers (PrPSc) of the host-encoded cellular prion protein (PrPC). PrPSc conformation to disease phenotype relationships extensively vary among prion strains. In particular, prions exhibit a strain-specific tropism for lymphoid tissues. Prions can be composed of several substrain components. There is evidence that these substrains can propagate in distinct tissues (e.g. brain and spleen) of a single individual, providing an experimental paradigm to study the cause of prion tissue selectivity. Previously, we showed that PrPC expression levels govern prion substrain selection in the brain. Transmission of sheep scrapie isolates (termed LAN) to multiple lines of transgenic mice expressing varying levels of ovine PrPC in the brain resulted in the phenotypic expression of the dominant sheep substrain in mice expressing near physiological PrPC levels, whereas a minor substrain replicated preferentially on high-expressors. Considering that PrPC expression levels are markedly decreased in the spleen compared to the brain, we interrogate whether spleen PrPC dosage could drive prion selectivity. The outcome of the transmission of a large cohort of LAN-like scrapie isolates in the spleen from high-expressors correlated with the replication rate dependency on PrPC amount; There was a prominent spleen colonization by the substrain preferentially replicating on low-expressors and a relative incapacity of the substrain with higher-PrPC level need to propagate in the spleen. Early colonization of the spleen allowed neuropathological expression of the lymphoid substrain after intraperitoneal inoculation. In addition, a pair of substrain variants resulting from the adaptation of human prions to ovine high-expressors, and exhibiting differing brain versus spleen tropism, showed different tropism on transmission to low-expressors, with the lymphoid substrain colonizing the brain. Overall, these data suggest that PrPC expression levels are instrumental in prion substrain lymphotropism. Author summaryThe cause of prion phenotype variation among prion strains remains poorly understood. In particular prions replicate in a strain-dependent manner in the spleen. This can result in prion asymptomatic carriers. Based on our previous observations that dosage of the prion precursor (PrP) determined prion substrain selection in the brain, we examine whether PrP levels in the spleen could drive prion replication in this tissue, due to the low levels of the protein. We observe that the prion substrain with higher PrP need for replication did barely replicate in the spleen, while the component with low PrP need replicated efficiently. In addition, other human co-propagating prions with differing spleen and brain tropism showed different tropism on transmission to mice expressing low PrP levels, with the lymphoid substrain colonizing the brain. PrPC expression levels may thus be instrumental in prion tropism for the lymphoid tissue. From a diagnostic point of view, given the apparent complexity of prion diseases with respect to prion substrain composition, these data advocate to type extraneural tissues or fluids for a comprehensive identification of the circulating prions in susceptible mammals.

pathology↗

bioRxiv2019

Complementation between pathological prion protein subassemblies to cross existing species barriers

Backgroundprion replication results from the autocatalytic templated assisted conversion of the host-encoded prion protein PrPC into misfolded, polydisperse PrPSc conformers. Structurally distinct PrPSc conformers can give rise to multiple prion strains. Within and between prion strains, the biological activity (replicative efficacy and specific infectivity) of PrPSc assemblies is size-dependent and thus reflects an intrinsic structural heterogeneity. The contribution of such PrPSc heterogeneity across species prion adaptation, - which is believed to be based on fit-adjustment between PrPSc template(s) and host PrPC -, has not been explored. Methodsto define the structural-to-fitness PrPSc landscape, we measured the relative capacity of size-fractionated PrPSc assemblies from different prion strains to cross mounting species barriers in transgenic mice expressing foreign PrPc. Resultsin the absence of a transmission barrier, the relative efficacy of the isolated PrPSc assemblies to induce the disease is superimposable to the efficacy observed in the homotypic context. However, in the presence of a transmission barrier, size fractionation overtly delays and even abrogates prion pathogenesis in both neural and extraneural, prion-permissive tissues, for reason independent of the infectivity load of the isolated assemblies. This suggests that a synergy between structurally distinct PrPSc assemblies in the inoculum is requested for crossing the species barrier. We further strengthen this hypothesis by showing that altering, by serial dilution, PrPSc assemblies content of unfractionated inocula reduce their specific infectivity in an aberrant manner, solely in the presence of a transmission barrier. Conclusionsour data support a mechanism whereby overcoming prion species barrier requires complementation between structurally distinct PrPSc assemblies. This work provides key insight into the "quasi-species" concept applied to prions, which would not necessarily rely on prion sub-strains as constituent but on structural PrPSc heterogeneity within prion population.

neuroscience↗

bioRxiv2019

Facilitating the propagation of spiking activity in feedforward networks by including feedback

Transient oscillations in the network activity upon sensory stimulation have been reported in different sensory areas. These evoked oscillations are the generic response of networks of excitatory and inhibitory neurons (EI-networks) to a transient external input. Recently, it has been shown that this resonance property of EI-networks can be exploited for communication in modular neuronal networks by enabling the transmission of sequences of synchronous spike volleys ( pulse packets), despite the sparse and weak connectivity between the modules. The condition for successful transmission is that the pulse packet (PP) intervals match the period of the modules resonance frequency. Hence, the mechanism was termed communication through resonance (CTR). This mechanism has three sever constraints, though. First, it needs periodic trains of PPs, whereas single PPs fail to propagate. Second, the inter-PP interval needs to match the network resonance. Third, transmission is very slow, because in each module, the network resonance needs to build-up over multiple oscillation cycles. Here, we show that, by adding appropriate feedback connections to the network, the CTR mechanism can be improved and the aforementioned constraints relaxed. Specifically, we show that adding feedback connections between two upstream modules, called the resonance pair, in an otherwise feedforward modular network can support successful propagation of a single PP throughout the entire network. The key condition for successful transmission is that the sum of the forward and backward delays in the resonance pair matches the resonance frequency of the network modules. The transmission is much faster, by more than a factor of two, than in the original CTR mechanism. Moreover, it distinctly lowers the threshold for successful communication by synchronous spiking in modular networks of weakly coupled networks. Thus, our results suggest a new functional role of bidirectional connectivity for the communication in cortical area networks.\n\nAuthor summaryThe cortex is organized as a modular system, with the modules (cortical areas) communicating via weak long-range connections. It has been suggested that the intrinsic resonance properties of population activities in these areas might contribute to enabling successful communication. A modules intrinsic resonance appears in the damped oscillatory response to an incoming spike volley, enabling successful communication during the peaks of the oscillation. Such communication can be exploited in feedforward networks, provided the participating networks have similar resonance frequencies. This, however, is not necessarily true for cortical networks. Moreover, the communication is slow, as it takes several oscillation cycles to build up the response in the downstream network. Also, only periodic trains of spikes volleys (and not single volleys) with matching intervals can propagate. Here, we present a novel mechanism that alleviates these shortcomings and enables propagation of synchronous spiking across weakly connected networks with not necessarily identical resonance frequencies. In this framework, an individual spike volley can propagate by local amplification through reverberation in a loop between two successive networks, connected by feedforward and feedback connections: the resonance pair. This overcomes the need for activity build-up in downstream networks, causing the volley to propagate distinctly faster and more reliably.

neuroscience↗

bioRxiv2019

Quaternary structural convergence and structural diversification of prion assemblies at the early replication stage

Aggregation of misfolded forms from host-encoded proteins is key to the pathogenesis of a number of neurodegenerative disorders, including prion diseases, Alzheimers disease and Parkinsons disease. In prion diseases, the cellular prion protein PrPC can misfold into PrPSc and auto-organize into conformationally distinct assemblies or strains. A plethora of observations reports the existence of PrPSc structural heterogeneity within prion strains, suggesting the emergence and coevolution of structurally distinct PrPSc assemblies during prion replication in controlled environment. Such PrPSc diversification processes remain poorly understood. Although central to prion host-adaptation, structural diversification of PrPSc assemblies is also a key issue for the formation of PrP conformers involved in neuronal injury. Here, we characterized the evolution of the PrPSc quaternary structure during prion replication in vivo and in bona fide cell-free amplification assays. Regardless of the strain studied, the early replication stage conduced to the preferential formation of small PrPSc oligomers, thus highlighting a quaternary structural convergence phenomenon. Their evolutionary kinetics revealed the existence of a PrPC-dependent secondary templating pathway in concert with a structural rearrangement. This secondary templating pathway provides, for the first time, a mechanistic explanation for prion structural diversification during replication, a key determinant for prion adaptation on further transmission, including to other host species. The uncovered processes are also key for a better understanding of the accumulation mechanisms of other misfolded assemblies believed to propagate by a prion-like process.

biochemistry↗