1,720,984 research outputs found
Study of alpha-synuclein fibrillation: State of the art and expectations
No full textSince the discovery of the presence of fibrillary forms of α-synuclein (α-syn) in Lewy bodies (LB) and Lewy neurites in the brain of patients affected by Parkinson’s disease (PD) and dementia with LB, great effort has been dedicated to study the features of α-syn fibrillation. In parallel, the pathological relevance of the different toxic forms of α-syn has been also matter of investigation. In the last twenty years, scientists have been able to single out that α-syn fibrillation initiates pathological mechanisms that by contributing to or triggering neurodegeneration/neuroinflammation, may lead to PD pathogenesis. This notwithstanding, we still ignore the reasons why α-syn shifts from its natively unfolded conformation to toxic oligomeric and fibrillary forms. The chameleonic nature of monomeric α-syn, and the extremely polymorphic characteristics of aggregated strains, renders it difficult to picture the real nature of α-syn fibrils, their exact composition and formation dynamics. Recently, sophisticated biophysical methods and microscopy techniques have been exploited to study α-syn fibrillation. Here, we provide an overview of the most relevant advancement in our understanding of α-syn fibrils formation and conformation. Nonetheless, numerous techniques and patient- derived experimental models still need to be optimized to actively disclose causes and characteristics of α-syn fibrillation in disease-specific cellular milieux
The good and bad of therapeutic strategies that directly target α-synuclein
No full textSynucleinopathies are neurodegenerative diseases characterized by the accumulation of either neuronal/axonal or glial insoluble proteinaceous aggregates mainly composed of α‐synuclein (α‐syn). Among them, the most common disorders are Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and some forms of familial parkinsonism. Both α‐syn fibrils and oligomers have been found to exert toxic effects on neurons or oligodendroglial cells, can activate neuroinflammatory responses, and mediate the spreading of α‐syn pathology. This poses the question of which is the most toxic α‐syn species. What is worst, α‐syn appears as a very peculiar protein, exerting multiple physiological functions in neurons, especially at synapses, but without acquiring a stable tertiary structure. Its conformation is particularly plastic, and the protein can exist in a natively unfolded state (mainly in solution), partially α‐helical folded state (when it interacts with biological membranes), or oligomeric state (tetramers or dimers with debated functional profile). The extent of α‐syn expression impinges on the resilience of neuronal cells, as multiplications of its gene locus, or overexpression, can cause neurodegeneration and onset of motor phenotype. For these reasons, one of the main challenges in the field of synucleinopathies, which still nowadays can only be managed by symptomatic therapies, has been the development of strategies aimed at reducing α‐syn levels, oligomer formation, fibrillation, or cell‐to‐cell transmission. This review resumes the therapeutic approaches that have been proposed or are under development to counteract α‐syn pathology by direct targeting of this protein and discuss their pros and cons in relation to the current state‐of‐the‐art α‐syn biology
Alpha synuclein post translational modifications: potential targets for Parkinson’s disease therapy?
Full text linkParkinson’s disease (PD) is the most common neurodegenerative disorder with motor symptoms. The neuropathological alterations characterizing the brain of patients with PD include the loss of dopaminergic neurons of the nigrostriatal system and the presence of Lewy bodies (LB), intraneuronal inclusions that are mainly composed of alpha-synuclein (α-Syn) fibrils. The accumulation of α-Syn in insoluble aggregates is a main neuropathological feature in PD and in other neurodegenerative diseases, including LB dementia (LBD) and multiple system atrophy (MSA), which are therefore defined as synucleinopathies. Compelling evidence supports that α-Syn post translational modifications (PTMs) such as phosphorylation, nitration, acetylation, O-GlcNAcylation, glycation, SUMOylation, ubiquitination and C-terminal cleavage, play important roles in the modulation α-Syn aggregation, solubility, turnover and membrane binding. In particular, PTMs can impact on α-Syn conformational state, thus supporting that their modulation can in turn affect α-Syn aggregation and its ability to seed further soluble α-Syn fibrillation. This review focuses on the importance of α-Syn PTMs in PD pathophysiology but also aims at highlighting their general relevance as possible biomarkers and, more importantly, as innovative therapeutic targets for synucleinopathies. In addition, we call attention to the multiple challenges that we still need to face to enable the development of novel therapeutic approaches modulating α-Syn PTMs
Design and Synthesis of Fluorescent Methylphenidate Analogues for a FRET-Based Assay of Synapsin III Binding
No full textWe previously described synapsin III (Syn III) as a synaptic phosphoprotein that controls dopamine release in cooperation with α-synuclein (aSyn). Moreover, we found that in Parkinson's disease (PD), Syn III also participates in aSyn aggregation and toxicity. Our recent observations point to threo-methylphenidate (MPH), a monoamine re-uptake inhibitor that efficiently counteracts the freezing-gait characteristic of advanced PD, as a ligand for Syn III. We have designed and synthesised two different fluorescently labelled MPH derivatives, one with Rhodamine Red (RHOD) and one with 5-carboxytetramethylrhodamine (TAMRA), to be used for assessing MPH binding to Syn III by FRET. TAMRA-MPH exhibited the ideal characteristics to be used as a FRET acceptor, as it was able to enter into the SK-N-SH cells and could interact specifically with human green fluorescent protein (GFP)-tagged Syn III but not with GFP alone. Moreover, the uptake of TAMRA-MPH and co-localization with Syn III was also observed in primary mesencephalic neurons. These findings support that MPH is a Syn III ligand and that TAMRA-conjugated drug molecules might be valuable tools to study drug-ligand interactions by FRET or to detect Syn III in cytological and histological samples
Validation of synapsin III as a therapeutic target for Parkinson’s disease in the AAV-mediated alpha-synuclein mouse model
No full textSynapsin III deficiency hampers α-synuclein aggregation, striatal synaptic damage and synaptic protein’s redistribution
No full textGoing Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
The Role of Rab Proteins in Parkinson's Disease Synaptopathy.
Full text linkIn patients affected by Parkinson's disease (PD), the most common neurodegenerative movement disorder, the brain is characterized by the loss of dopaminergic neurons in the nigrostriatal system, leading to dyshomeostasis of the basal ganglia network activity that is linked to motility dysfunction. PD mostly arises as an age-associated sporadic disease, but several genetic forms also exist. Compelling evidence supports that synaptic damage and dysfunction characterize the very early phases of either sporadic or genetic forms of PD and that this early PD synaptopathy drives retrograde terminal-to-cell body degeneration, culminating in neuronal loss. The Ras-associated binding protein (Rab) family of small GTPases, which is involved in the maintenance of neuronal vesicular trafficking, synaptic architecture and function in the central nervous system, has recently emerged among the major players in PD synaptopathy. In this manuscript, we provide an overview of the main findings supporting the involvement of Rabs in either sporadic or genetic PD pathophysiology, and we highlight how Rab alterations participate in the onset of early synaptic damage and dysfunction
An updated reappraisal of synapsins: structure, function and role in neurological and psychiatric disorders
No full textSynapsins (Syns) are phosphoproteins strongly involved in neuronal development and neurotransmitter release. Three distinct genes SYN1, SYN2 and SYN3, with elevated evolutionary conservation, have been described to encode for Synapsin I, Synapsin II and Synapsin III, respectively. Syns display a series of common features, but also exhibit distinctive localization, expression pattern, post-translational modifications (PTM). These characteristics enable their interaction with other synaptic proteins, membranes and cytoskeletal components, which is essential for the proper execution of their multiple functions in neuronal cells. These include the control of synapse formation and growth, neuron maturation and renewal, as well as synaptic vesicle mobilization, docking, fusion, recycling. Perturbations in the balanced expression of Syns, alterations of their PTM, mutations and polymorphisms of their encoding genes induce severe dysregulations in brain networks functions leading to the onset of psychiatric or neurological disorders. This review presents what we have learned since the discovery of Syn I in 1977, providing the state of the art on Syns structure, function, physiology and involvement in central nervous system disorders
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