Niccolò Candelise

Bio: Niccolò Candelise is an academic researcher from National Research Council. The author has contributed to research in topics: Protein aggregation. The author has an hindex of 1, co-authored 1 publications receiving 5 citations.

Protein Aggregation Landscape in Neurodegenerative Diseases: Clinical Relevance and Future Applications.

Abstract: Intrinsic disorder is a natural feature of polypeptide chains, resulting in the lack of a defined three-dimensional structure. Conformational changes in intrinsically disordered regions of a protein lead to unstable β-sheet enriched intermediates, which are stabilized by intermolecular interactions with other β-sheet enriched molecules, producing stable proteinaceous aggregates. Upon misfolding, several pathways may be undertaken depending on the composition of the amino acidic string and the surrounding environment, leading to different structures. Accumulating evidence is suggesting that the conformational state of a protein may initiate signalling pathways involved both in pathology and physiology. In this review, we will summarize the heterogeneity of structures that are produced from intrinsically disordered protein domains and highlight the routes that lead to the formation of physiological liquid droplets as well as pathogenic aggregates. The most common proteins found in aggregates in neurodegenerative diseases and their structural variability will be addressed. We will further evaluate the clinical relevance and future applications of the study of the structural heterogeneity of protein aggregates, which may aid the understanding of the phenotypic diversity observed in neurodegenerative disorders.

Revisiting the grammar of Tau aggregation and pathology formation: how new insights from brain pathology are shaping how we study and target Tauopathies

Abstract: Converging evidence continues to point towards Tau aggregation and pathology formation as central events in the pathogenesis of Alzheimer's disease and other Tauopathies. Despite significant advances in understanding the morphological and structural properties of Tau fibrils, many fundamental questions remain about what causes Tau to aggregate in the first place. The exact roles of cofactors, Tau post-translational modifications, and Tau interactome in regulating Tau aggregation, pathology formation, and toxicity remain unknown. Recent studies have put the spotlight on the wide gap between the complexity of Tau structures, aggregation, and pathology formation in the brain and the simplicity of experimental approaches used for modeling these processes in research laboratories. Embracing and deconstructing this complexity is an essential first step to understanding the role of Tau in health and disease. To help deconstruct this complexity and understand its implication for the development of effective Tau targeting diagnostics and therapies, we firstly review how our understanding of Tau aggregation and pathology formation has evolved over the past few decades. Secondly, we present an analysis of new findings and insights from recent studies illustrating the biochemical, structural, and functional heterogeneity of Tau aggregates. Thirdly, we discuss the importance of adopting new experimental approaches that embrace the complexity of Tau aggregation and pathology as an important first step towards developing mechanism- and structure-based therapies that account for the pathological and clinical heterogeneity of Alzheimer's disease and Tauopathies. We believe that this is essential to develop effective diagnostics and therapies to treat these devastating diseases.

Insight into membraneless organelles and their associated proteins: Drivers, Clients and Regulators.

Abstract: In recent years, attention has been devoted to proteins forming immiscible liquid phases within the liquid intracellular medium, commonly referred to as membraneless organelles (MLO). These organelles enable the spatiotemporal associations of cellular components that exchange dynamically with the cellular milieu. The dysregulation of these liquid-liquid phase separation processes (LLPS) may cause various diseases including neurodegenerative pathologies and cancer, among others. Until very recently, databases containing information on proteins forming MLOs, as well as tools and resources facilitating their analysis, were missing. This has recently changed with the publication of 4 databases that focus on different types of experiments, sets of proteins, inclusion criteria, and levels of annotation or curation. In this study we integrate and analyze the information across these databases, complement their records, and produce a consolidated set of proteins that enables the investigation of the LLPS phenomenon. To gain insight into the features that characterize different types of MLOs and the roles of their associated proteins, they were grouped into categories: High Confidence MLO associated (including Drivers and reviewed proteins), Potential Clients and Regulators, according to their annotated functions. We show that none of the databases taken alone covers the data sufficiently to enable meaningful analysis, validating our integration effort as essential for gaining better understanding of phase separation and laying the foundations for the discovery of new proteins potentially involved in this important cellular process. Lastly, we developed a server, enabling customized selections of different sets of proteins based on MLO location, database, disorder content, among other attributes (https://forti.shinyapps.io/mlos/).

Role of ERLINs in the Control of Cell Fate through Lipid Rafts.

Abstract: ER lipid raft-associated protein 1 (ERLIN1) and 2 (ERLIN2) are 40 kDa transmembrane glycoproteins belonging to the family of prohibitins, containing a PHB domain. They are generally localized in the endoplasmic reticulum (ER), where ERLIN1 forms a heteroligomeric complex with its closely related ERLIN2. Well-defined functions of ERLINS are promotion of ER-associated protein degradation, mediation of inositol 1,4,5-trisphosphate (IP3) receptors, processing and regulation of lipid metabolism. Until now, ERLINs have been exclusively considered protein markers of ER lipid raft-like microdomains. However, under pathophysiological conditions, they have been described within mitochondria-associated endoplasmic reticulum membranes (MAMs), tethering sites between ER and mitochondria, characterized by the presence of specialized raft-like subdomains enriched in cholesterol and gangliosides, which play a key role in the membrane scrambling and function. In this context, it is emerging that ER lipid raft-like microdomains proteins, i.e., ERLINs, may drive mitochondria-ER crosstalk under both physiological and pathological conditions by association with MAMs, regulating the two main processes underlined, survival and death. In this review, we describe the role of ERLINs in determining cell fate by controlling the “interchange” between apoptosis and autophagy pathways, considering that their alteration has a significant impact on the pathogenesis of several human diseases.