Michele Vendruscolo

University of Cambridge | Cam · Department of Chemistry

Tau pathology is a hallmark of several neurodegenerative diseases, including frontotemporal dementia and Alzheimer’s disease. However, the sequence of events and the form of tau that confers toxicity are still unclear, due in large part to the lack of physiological models of tauopathy initiation and progression in which to test hypotheses. We have...

The protein homeostasis (proteostasis) system maintains the proteome in a healthy state. Although this system has been comprehensively mapped, its perturbations in disease remain incompletely characterised. To address this problem, here we define the proteostasis signatures, which represent the characteristic patterns of change in the proteostasis...

Advances in solid-state nuclear magnetic resonance (ssNMR) spectroscopy and cryogenic electron microscopy (cryoEM) have revealed the polymorphic nature of the amyloid state of proteins. Given the association of amyloid with protein misfolding disorders, it is important to understand the principles underlying this polymorphism. To address this probl...

In computational physics, chemistry, and biology, the implementation of new techniques in a shared and open source software lowers barriers to entry and promotes rapid scientific progress. However, effectively training new software users presents several challenges. Common methods like direct knowledge transfer and in-person workshops are limited i...

Molecular Dynamics (MD) simulations provide accurate descriptions of the motions of molecular systems, yet their computational demands pose significant challenges in applications in molecular biology and materials science. Given the success of deep learning methods in a wide range of fields, a timely question concerns whether these methods could be...

Many proteins have been recently shown to undergo a process of phase separation that leads to the formation of biomolecular condensates. Intriguingly, it has been observed that some of these proteins form dense droplets of sizeable dimensions already below the critical concentration, which is the concentration at which phase separation occurs. To u...

Membraneless organelles (MLOs) are dynamic macromolecular condensates that act as crucibles to modulate biological process within the cell. Since MLOs form in the absence of lipid membranes, it is important to understand how their effective regulation is achieved by the protein homeostasis (proteostasis) system. To address this question, we report...

Deep learning methods of predicting protein structures have reached an accuracy comparable to that of high-resolution experimental methods. It is thus possible to generate accurate models of the native states of hundreds of millions of proteins. An open question, however, concerns whether these advances can be translated to disordered proteins, whi...

The aggregation of α -synuclein into amyloid fibrils is a hallmark of Parkinson’s disease. This process has been shown to directly involve interactions between proteins and lipid surfaces when the latter are present. Despite this importance, the molecular mechanisms of lipid-induced amyloid aggregation have remained largely elusive. Here, we presen...

The deposition of the amyloid-β (Aβ) peptide into amyloid fibrils is a hallmark of Alzheimer’s disease. Recently, it has been reported that some proteins can aggregate and form amyloids through an intermediate pathway involving a liquid-like condensed phase. These observations prompted us to investigate the phase space of Aβ. We thus explored the a...

Amyloids are associated with over 50 human diseases and have inspired significant effort to identify small molecule remedies. Here, we present an in vivo platform that efficiently yields small molecule inhibitors of amyloid formation. We previously identified small molecules that kill the nematode C. elegans by forming membrane-piercing crystals in...

Sporadic Alzheimer's disease (sAD) arises from a complex interplay between genetic and environmental factors that remains poorly understood, making it challenging to develop accurate cell models. To address this problem, by hypothesing that the early disease sAD states can be characterised by transcriptomic fingerprints, we assessed the effect on A...

Alzheimer's disease (AD) patients exhibit an increased load of Aβ aggregates in the brain parenchyma. The neurotoxic nature of these aggregates has been underscored by recent advances in therapies aimed at reducing their load. To make further progress towards the development of increasingly effective treatments, there is a still largely unmet need...

The aggregation of Aβ42 into misfolded oligomers is a central event in the pathogenesis of Alzheimer's disease. In this study, we aimed to develop a robust experimental system that recapitulates Aβ42 oligomerization in living cells to gain insight into their neurotoxicity and to provide a platform to characterize the effects of inhibitors of this p...

Nanogels offer unique advantages, like high surface-to-volume ratio, scalable synthetic methods and easily tailored formulations, that allow to control size and introduce stimuli-responsive properties. Their potential for drug delivery is significant due to their biocompatibility, high drug loading capacity, and controlled and sustained drug releas...

Oligomeric species arising during the aggregation of α-synuclein are implicated as a major source of toxicity in Parkinson’s disease, and thus a major potential drug target. However, both their mechanism of formation and role in aggregation are largely unresolved. Here we show that, at physiological pH and in the absence of lipid membranes, α-synuc...

The process of protein phase separation into liquid condensates has been implicated in the formation of membraneless organelles (MLOs), which selectively concentrate biomolecules to perform essential cellular functions. Although the importance of this process in health and disease is increasingly recognized, the experimental identification of prote...

Many proteins have been recently shown to undergo a process of phase separation that leads to the formation of biomolecular condensates. Intriguingly, it has been observed that some of these proteins form dense droplets of sizeable dimensions already below the critical concentration, which is the concentration at which phase separation occurs. To u...

Cryogenic electron microscopy (cryo-EM) has emerged as a powerful method for the determination of structures of complex biological molecules. The accurate characterisation of the dynamics of such systems, however, remains a challenge. To address this problem, we introduce cryoENsemble, a method that applies Bayesian reweighting to conformational en...

The process of protein misfolding and aggregation is associated with various cytotoxic effects. Understanding how this phenomenon is regulated by the protein homeostasis system, however, is difficult, since it takes place through a complex non-linear network of coupled microscopic steps, including primary nucleation, fibril elongation, and secondar...

The endoplasmic reticulum (ER) plays key roles in protein quality control and dynamic Ca2+> storage in eukaryotic cells. However, the protein homeostasis (proteostasis) system that regulates these ER functions is still incompletely characterised. Previous study revealed the importance of oligomerization in the function PDIA1, an ER-resident disulfi...

Aβ oligomers are being investigated as cytotoxic agents in Alzheimer’s disease (AD). Because of their transient nature and conformational heterogeneity, the relationship between the structure and activity of these oligomers is still poorly understood. Hence, methods for stabilizing Aβ oligomeric species relevant to AD are needed to uncover the stru...

Recent advances in machine learning methods for materials science have significantly enhanced accurate predictions of the properties of novel materials. Here, we explore whether these advances can be adapted to drug discovery by addressing the problem of prospective validation - the assessment of the performance of a method on out-of-distribution d...

Alzheimer’s disease is characterized by the aggregation of the Aβ peptide into amyloid fibrils. According to the amyloid hypothesis, targeting pharmacologically Aβ aggregation could result in disease-modifying treatments. The identification of inhibitors of Aβ aggregation, however, is complicated by complex technical challenges, which typically res...

The role of the SNCA gene locus in driving Parkinsons disease (PD) through rare and common genetic variation is well-recognized, but the transcriptional diversity of SNCA in vulnerable cell types remains unclear. We performed SNCA long-read RNA sequencing in human dopaminergic neurons and show that annotated SNCA transcripts account for only 5% of...

Aggregated forms of α-synuclein constitute the major component of Lewy bodies, the proteinaceous aggregates characteristic of Parkinson’s disease. Emerging evidence suggests that α-synuclein aggregation may occur within liquid condensates formed through phase separation. This mechanism of aggregation creates new challenges and opportunities for dru...

Machine learning methods hold the promise to reduce the costs and the failure rates of conventional drug discovery pipelines. This issue is especially pressing for neurodegenerative diseases, where the development of disease-modifying drugs has been particularly challenging. To address this problem, we describe here a machine learning approach to i...

Nanogels offer unique advantages, like high surface-to-volume ratio, scalable synthetic methods and easily tailored formulations, that allow to control size and introduce stimuli-responsive properties. Their potential for drug delivery is significant due to their biocompatibility, high drug loading capacity, and controlled and sustained drug releas...

Super-resolution and single-molecule microscopies have been increasingly applied to complex biological systems. A major challenge of these approaches is that fluorescent puncta must be detected in the low signal, high noise, heterogeneous background environments of cells and tissue. We present RASP, Radiality Analysis of Single Puncta, a bioimaging...

Allosteric cooperativity between ATP and substrates is a prominent characteristic of the cAMP-dependent catalytic subunit of protein kinase A (PKA). Not only this long-range synergistic action is involved in substrate recognition and fidelity, but it is also likely to regulate PKA association with regulatory subunits and other binding partners. To...

Oligomeric assemblies of the amyloid β peptide (Aβ) have been investigated for over two decades as possible neurotoxic agents in Alzheimer’s disease. However, due to their heterogeneous and transient nature, it is not yet fully established which of the structural features of these oligomers may generate cellular damage. Here, we study distinct olig...

The conversion of native peptides and proteins into amyloid aggregates is a hallmark of over 50 human disorders, including Alzheimer’s and Parkinson’s diseases. Increasing evidence implicates misfolded protein oligomers produced during the amyloid formation process as the primary cytotoxic agents in many of these devastating conditions. In this rev...

Parkinson's disease (PD) is a common neurodegenerative condition characterised by the presence in the brain of large intraneuronal aggregates, known as Lewy bodies and Lewy neurites, containing fibrillar α-synuclein. According to the amyloid hypothesis, these large end-stage species form from smaller soluble protein assemblies, often termed oligome...

The chemical modification of proteins is one of the major mechanisms used to regulate the properties and functions of these macromolecules in the cell. It is therefore of great interest to develop tools to exploit this type of modifications for applications in molecular biology, medicine and biotechnology. Here we present a method of using antibodi...

The misfolding and aggregation of α-synuclein is linked to a family of neurodegenerative disorders known as synucleinopathies, the most prominent of which is Parkinson’s disease (PD). Understanding the aggregation process of α-synuclein from a mechanistic point of view is thus of key importance. SNCA , the gene encoding α-synuclein, comprises six e...

Many proteins have been recently shown to undergo a process of phase separation that leads to the formation of biomolecular condensates. Intriguingly, it has been observed that some of these proteins form dense droplets of sizeable dimensions already below the transition concentration, which is the concentration at which phase separation occurs. To...

Many proteins have been recently shown to undergo a process of phase separation that leads to the formation of biomolecular condensates. Intriguingly, it has been observed that some of these proteins form dense droplets of sizeable dimensions already below the transition concentration, which is the concentration at which phase separation occurs. To...

Many proteins self-assemble to form amyloid fibrils, which are highly organized structures stabilized by a characteristic cross-β network of hydrogen bonds. This process underlies a variety of human diseases and can be exploited to develop versatile functional biomaterials. Thus, protein self-assembly has been widely studied to shed light on the pr...

The amyloid beta peptide (Abeta) readily aggregates into amyloid fibrils. This process has been the subject of intense investigations since it is associated with Alzheimers disease. However, it has been highly challenging to observe the microscopic steps in the aggregation reaction directly and to characterize the oligomeric assemblies formed as in...

A wide range of human disorders, including Alzheimer’s disease (AD), are characterised by the aberrant formation of amyloid fibrils. Amyloid fibrils are filamentous structures characterized by the presence of a highly-ordered cross-β core. In many cases, this core structure is flanked by disordered regions, often referred to as fuzzy coat. The stru...

In the early stages of drug development, large chemical libraries are typically screened to identify compounds of promising potency against the chosen targets. Often, however, the resulting hit compounds tend to have poor drug metabolism and pharmacokinetics (DMPK), with negative developability features that may be difficult to eliminate. Therefore...

The onset and development of Alzheimer’s disease (AD) is linked to the accumulation of pathological aggregates formed from the normally monomeric amyloid-β peptide within the central nervous system. These Aβ aggregates are increasingly successfully targeted with clinical therapies, but the fundamental molecular steps that trigger the initial nuclea...

A wide range of human disorders, including Alzheimer's disease (AD), are characterised by the aberrant formation of amyloid fibrils. Amyloid fibrils are filamentous structures characterized by the presence of a highly-ordered cross-β core. In many cases, this core structure is flanked by disordered regions, often referred to as fuzzy coat. The stru...

Background The microtubule‐associated protein tau is implicated in the development of a class of diverse neurodegenerative disorders, referred to as tauopathies, with symptoms of dementia and parkinsonism. Tauopathies comprise more than 20 clinicopathological entities, including Alzheimer’s disease, which accounts for 70% of dementia cases worldwid...

Background Emerging evidence indicates leucine‐rich repeat kinase 2 (LRRK2) may be involved in tau uptake and spread throughout the brain. Microglia, the brain‐resident phagocytes, become one of the highest LRRK2 expressing cells under inflammatory conditions. Rodent microglia were also shown capable of secreting seeding‐competent tau into the extr...

The deposition of the Abeta peptide into amyloid fibrils is characteristic of Alzheimer's disease. As it has been recently observed that the process of amyloid aggregation can take place within an intermediate liquid-like condensed phase, we investigated whether Abeta could undergo liquid-liquid phase separation, and whether Abeta amyloid aggregati...

In addition to the native state, proteins can form liquid-like condensates, viscoelastic condensates, such as gels, as well as solid-like condensates, such as amyloid fibrils, crystals and amorphous materials. The material properties of these condensates play important roles in their cellular functions, with aberrant liquid-to-solid phase transitio...

The process of drug design requires the initial identification of compounds that bind their targets with high affinity and selectivity. Advances in generative modeling of small molecules based on deep learning are offering novel opportunities for making this process faster and cheaper. Here, we propose an approach to achieve this goal, where predic...

Super-resolution and single-molecule microscopy are increasingly applied to complex biological systems. A major challenge of this approach is that fluorescent puncta must be detected in the low signal, high noise, heterogeneous background environments of cells and tissue. We present RASP, Radiality Analysis of Single Puncta, a bioimaging-segmentati...

Protein-ligand interactions play central roles in biological processes and are of key importance in drug design 1,2 . Deep learning approaches hold the promise of becoming cost-effective alternatives to high-throughput experimental methods for ligand identification ³⁻⁶ . Here, to predict the binding affinity between proteins and small molecules, we...

Protein-ligand interactions play central roles in biological processes and are of key importance in drug design. Deep learning-based approaches are emerging as cost-effective alternatives to high-throughput experimental methods for the screening of large libraries of ligands. Here, to predict the binding affinity between proteins and small molecule...

Cryogenic electron microscopy (cryo-EM) has emerged as a central tool for the determination of structures of complex biological molecules. Accurately characterising the dynamics of such systems, however, remains a challenge. To address this, we introduce cryoENsemble, a method that applies Bayesian reweighing to conformational ensembles derived fro...

Non-natural amino acids are increasingly used as building blocks in the development of peptide-based drugs as they expand the available chemical space to tailor function, half-life and other key properties. However, while the chemical space of modified amino acids (mAAs) such as residues containing post-translational modifications (PTMs) is potenti...

Misfolded protein oligomers are of central importance in both the diagnosis and treatment of Alzheimer’s and Parkinson’s diseases. However, accurate high-throughput methods to detect and quantify oligomer populations are still needed. We present here a single-molecule approach for the detection and quantification of oligomeric species. The approach...

Allosteric cooperativity between ATP and substrates is a prominent characteristic of the cAMP-dependent catalytic (C) subunit of protein kinase A (PKA). Not only this long-range synergistic action is involved in substrate recognition and fidelity, but it is likely to regulate PKA association with regulatory subunits and other binding partners. To d...

Allosteric cooperativity between ATP and substrates is a prominent characteristic of the cAMP-dependent catalytic (C) subunit of protein kinase A (PKA). Not only this long-range synergistic action is involved in substrate recognition and fidelity, but it is likely to regulate PKA association with regulatory subunits and other binding partners. To d...

The phenomenon of protein phase separation (PPS) underlies a wide range of cellular functions. Correspondingly, the dysregulation of the PPS process has been associated with numerous human diseases. To enable therapeutic interventions based on the regulation of this association, possible targets should be identified. For this purpose, we present an...

Aggregated forms of α-synuclein constitute the major component of Lewy bodies, the proteinaceous aggregates characteristic of Parkinson’s disease1,2. Emerging evidence suggests that α-synuclein aggregation may occur within liquid condensates formed through phase separation³⁻⁵. This mechanism of aggregation creates new challenges and opportunites fo...

Allosteric cooperativity between ATP and substrates is a prominent characteristic of the cAMP-dependent catalytic (C) subunit of protein kinase A (PKA). Not only this long-range syn-ergistic action is involved in substrate recognition and fidelity, but it is likely to regulate PKA as-sociation with regulatory subunits and other binding partners. To...

The purpose of this symposium is to bring established investigators, junior researchers and industrials together to discuss and expand this exciting field. Attendance will be limited, making it an ideal setting for discussion and learning. The scientific program includes talks by the top international experts in the field as well as in-depth discu...

Parkinson’s disease is characterised by the deposition in the brain of amyloid aggregates of α-synuclein. The surfaces of these amyloid aggregates can catalyse the formation of new aggregates, giving rise to a positive feedback mechanism responsible for the rapid proliferation of α-synuclein deposits. We report a procedure to enhance the potency of...

The accurate recapitulation in an in vitro assay of the aggregation process of α-synuclein in Parkinson's disease has been a significant challenge. As α-synuclein does not aggregate spontaneously in most currently used in vitro assays, primary nucleation is triggered by the presence of surfaces such as lipid membranes or interfaces created by shaki...

Misfolded protein oligomers are of central importance in both the detection and treatment of Alzheimer's and Parkinson's diseases. However, accurate high-throughput methods to identify and quantify oligomer populations are currently lacking. We present here a single-molecule approach for the detection of oligomeric species. The approach is based on...

The aggregation of the protein tau into amyloid fibrils is associated with Alzheimer’s disease and related tauopathies. Since different tauopathies are characterised by the formation of distinct tau fibril polymorphs, it is important to develop in vitro tau aggregation assays that recapitulate the mechanism of tau aggregation in the brain, resultin...

The chemical modification of proteins is one of the major mechanisms used to regulate the trafficking and function of these macromolecules in the cell. It is therefore of great interest to develop tools to exploit this type of modifications for applications in molecular biology, medicine and biotechnology. Here we present a method of using antibodi...

In recent years, major advances in cryo-electron microscopy (cryo-EM) have enabled the routine determination of complex biomolecular structures at atomistic resolution. An open challenge for this approach, however, concerns large systems that exhibit continuous dynamics. To address this problem, we developed the metadynamic electron microscopy meta...

Natural aminosterols are promising drug candidates against neurodegenerative diseases, like Alzheimer and Parkinson, and one relevant protective mechanism occurs via their binding to biological membranes and displacement or binding inhibition of amyloidogenic proteins and their cytotoxic oligomers. We compared three chemically different aminosterol...

Introduction: Protein misfolding diseases, including Alzheimer's and Parkinson's diseases, are characterized by the aberrant aggregation of proteins. These conditions are still largely untreatable, despite having a major impact on our healthcare systems and societies. Areas covered: We describe drug discovery strategies to target protein misfold...

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are distinct clinicopathological subtypes of frontotemporal lobar degeneration. They both have atypical parkinsonism, and they usually have distinct clinical features. The most common clinical presentation of PSP is Richardson syndrome, and the most common presentation of CBD...