Sirtuins are an evolutionarily conserved family of NAD+ -dependent deacylases that display diversity in subcellular localization and function. SIRT2, the predominantly cytosolic sirtuin, is among the ...least understood of the seven mammalian sirtuin isoforms described (SIRT1–7). The purpose of this review is to summarize the most recent findings about the potential roles and effects of SIRT2 in mammalian metabolic homeostasis. We discuss the different functions and targets of SIRT2 in various physiological processes, including adipogenesis, fatty acid oxidation, gluconeogenesis, and insulin sensitivity. We also cover the role of SIRT2 in inflammation and oxidative stress due to the possible implications for metabolic disorders. Finally, we consider its potential as a therapeutic target for the prevention and treatment of type 2 diabetes.
In protein aggregation disorders, we assume that, during the process of protein aggregation, different types of aggregated species (oligomers, protofibrils, fibrils, etc.) are formed, some of which ...can be toxic to cells/tissues/organs. Recent evidence from numerous studies in cell and animal models of disease suggest that oligomeric species of different proteins might be more toxic that the larger, fibrillar forms. However, we still lack definitive data on the nature of the toxic species, mostly due to our inability to detect and define the various protein species that form as protein aggregate. The terms used are often broad and do not capture inter-laboratory variation in protocols and methods used for the characterization of aggregates. Even antibody-based methods can be ambiguous, as antibodies are delicate tools. Therefore, systematic and interdisciplinary studies are essential in order to guide future developments in the field.
The courage to change science Outeiro, Tiago Fleming
EMBO reports,
04 March 2020, Letnik:
21, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Bureaucracy, performance assessment and other pressures increasingly encroach on scientists’ ability to do science. The research community as a whole needs to address these perils.
Alzheimer's disease (AD) and Parkinson's disease (PD) are age-associated neurodegenerative disorders characterized by the misfolding and aggregation of alpha-synuclein (aSyn) and tau, respectively. ...The coexistence of aSyn and tau aggregates suggests a strong overlap between tauopathies and synucleinopathies. Interestingly, misfolded forms of aSyn and tau can propagate from cell to cell, and throughout the brain, thereby templating the misfolding of native forms of the proteins. The exact mechanisms involved in the propagation of the two proteins show similarities, and are reminiscent of the spreading characteristic of prion diseases. Recently, several models were developed to study the spreading of aSyn and tau. Here, we discuss the mechanisms involved, the similarities and differences between the spreading of the two proteins and that of the prion protein, and the different cell and animal models used for studying these processes. Ultimately, a deeper understanding of the molecular mechanisms involved may lead to the identification of novel targets for therapeutic intervention in a variety of devastating neurodegenerative diseases.
Alpha‐Synuclein (α‐Synuclein) is a 140 amino acid protein implicated in neurodegenerative disorders known as synucleinopathies, where it accumulates in proteinaceous inclusions in the brain. The ...normal physiological function of α‐Synuclein remains obscure, as it exists in several non‐neuronal cells in which its function has not been studied. Given the tremendous interest in studying α‐Synuclein, and the existing limitations in the production of modified forms of the protein, we developed a method for the chemical synthesis of α‐Synuclein by combining peptide fragment synthesis via automated microwave‐assisted solid‐phase peptide synthesis and ligation strategies. Our synthetic pathway enables the synthesis of protein variants of interest, carrying either mutations or posttranslational modifications, for further investigations of the effects on the structure and aggregation behavior of the protein. Ultimately, our study forms the foundation for future syntheses and studies of other custom‐made α‐Synuclein variants with a single or several modifications, as necessary.
The aggregation of alpha‐Synuclein, a protein associated with several neurodegenerative diseases, can be altered by mutations and by posttranslational modifications, but the precise effects of these alterations are still elusive. Here, we devised a strategy for the chemical synthesis of the protein combining solid‐phase peptide synthesis and native chemical ligation. This enables the synthesis of custom‐made protein variants to determine their aggregation behavior.
Alpha-synuclein (aSyn) was identified as the main component of inclusions that define synucleinopathies more than 20 years ago. Since then, aSyn has been extensively studied in an attempt to unravel ...its roles in both physiology and pathology. Today, studying the mechanisms of aSyn toxicity remains in the limelight, leading to the identification of novel pathways involved in pathogenesis. In this chapter, we address the molecular mechanisms involved in synucleinopathies, from aSyn misfolding and aggregation to the various cellular effects and pathologies associated. In particular, we review our current understanding of the mechanisms involved in the spreading of aSyn between different cells, from the periphery to the brain, and back. Finally, we also review recent studies on the contribution of inflammation and the gut microbiota to pathology in synucleinopathies. Despite significant advances in our understanding of the molecular mechanisms involved, we still lack an integrated understanding of the pathways leading to neurodegeneration in PD and other synucleinopathies, compromising our ability to develop novel therapeutic strategies.
Parkinson's disease belongs to a group of currently incurable neurodegenerative disorders characterized by the misfolding and accumulation of alpha‐synuclein aggregates that are commonly known as ...synucleinopathies. Clinically, synucleinopathies are heterogeneous, reflecting the somewhat selective neuronal vulnerability characteristic of each disease. The precise molecular underpinnings of synucleinopathies remain unclear, but the process of aggregation of alpha‐synuclein appears as a central event. However, there is still no consensus with respect to the toxic forms of alpha‐synuclein, hampering our ability to use the protein as a target for therapeutic intervention. To decipher the molecular bases of synucleinopathies, it is essential to understand the complex triangle formed between the structure, function and toxicity of alpha‐synuclein. Recently, important steps have been undertaken to elucidate the role of the protein in both physiological and pathological conditions. Here, we provide an overview of recent findings in the field of alpha‐synuclein research, and put forward a new perspective over paradigms that persist in the field. Establishing whether alpha‐synuclein has a causative role in all synucleinopathies will enable the identification of targets for the development of novel therapeutic strategies for this devastating group of disorders.
Alpha‐synuclein is the speculated cornerstone of several neurodegenerative disorders known as Synucleinopathies. Nevertheless, the mechanisms underlying the pathogenic effects of this protein remain unknown. Here, we review the recent findings in the three corners of alpha‐synuclein biology – structure, function and toxicity – and discuss the enigmatic roads that have accompanied alpha‐synuclein from the beginning.
This article is part of a special issue on Parkinson disease.
Alpha‐synuclein is the speculated cornerstone of several neurodegenerative disorders known as Synucleinopathies. Nevertheless, the mechanisms underlying the pathogenic effects of this protein remain unknown. Here, we review the recent findings in the three corners of alpha‐synuclein biology – structure, function and toxicity – and discuss the enigmatic roads that have accompanied alpha‐synuclein from the beginning.
This article is part of a special issue on Parkinson disease.
PDF
