| 1. |
- De Mattos, Eduardo P., et al.
(författare)
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Protein Quality Control Pathways at the Crossroad of Synucleinopathies
- 2020
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Ingår i: Journal of Parkinson's Disease. - 1877-7171. ; 10:2, s. 369-382
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Forskningsöversikt (refereegranskat)abstract
- The pathophysiology of Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and many others converge at alpha-synuclein (α-Syn) aggregation. Although it is still not entirely clear what precise biophysical processes act as triggers, cumulative evidence points towards a crucial role for protein quality control (PQC) systems in modulating α-Syn aggregation and toxicity. These encompass distinct cellular strategies that tightly balance protein production, stability, and degradation, ultimately regulating α-Syn levels. Here, we review the main aspects of α-Syn biology, focusing on the cellular PQC components that are at the heart of recognizing and disposing toxic, aggregate-prone α-Syn assemblies: molecular chaperones and the ubiquitin-proteasome system and autophagy-lysosome pathway, respectively. A deeper understanding of these basic protein homeostasis mechanisms might contribute to the development of new therapeutic strategies envisioning the prevention and/or enhanced degradation of α-Syn aggregates.
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| 2. |
- Guo, Jian Jun, et al.
(författare)
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Intranasal administration of α-synuclein preformed fibrils triggers microglial iron deposition in the substantia nigra of Macaca fascicularis
- 2021
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Ingår i: Cell Death and Disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Iron deposition is present in main lesion areas in the brains of patients with Parkinson’s disease (PD) and an abnormal iron content may be associated with dopaminergic neuronal cytotoxicity and degeneration in the substantia nigra of the midbrain. However, the cause of iron deposition and its role in the pathological process of PD are unclear. In the present study, we investigated the effects of the nasal mucosal delivery of synthetic human α-synuclein (α-syn) preformed fibrils (PFFs) on the pathogenesis of PD in Macaca fascicularis. We detected that iron deposition was clearly increased in a time-dependent manner from 1 to 17 months in the substantia nigra and globus pallidus, highly contrasting to other brain regions after treatments with α-syn PFFs. At the cellular level, the iron deposits were specifically localized in microglia but not in dopaminergic neurons, nor in other types of glial cells in the substantia nigra, whereas the expression of transferrin (TF), TF receptor 1 (TFR1), TF receptor 2 (TFR2), and ferroportin (FPn) was increased in dopaminergic neurons. Furthermore, no clear dopaminergic neuron loss was observed in the substantia nigra, but with decreased immunoreactivity of tyrosine hydroxylase (TH) and appearance of axonal swelling in the putamen. The brain region-enriched and cell-type-dependent iron localizations indicate that the intranasal α-syn PFFs treatment-induced iron depositions in microglia in the substantia nigra may appear as an early cellular response that may initiate neuroinflammation in the dopaminergic system before cell death occurs. Our data suggest that the inhibition of iron deposition may be a potential approach for the early prevention and treatment of PD.
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| 3. |
- Negrini, Matilde, et al.
(författare)
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Sequential or Simultaneous Injection of Preformed Fibrils and AAV Overexpression of Alpha-Synuclein Are Equipotent in Producing Relevant Pathology and Behavioral Deficits
- 2022
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Ingår i: Journal of Parkinson's Disease. - 1877-7171. ; 12:4, s. 1133-1153
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Tidskriftsartikel (refereegranskat)abstract
- Background: Preclinical rodent models for Parkinson's disease (PD) based on viral human alpha-synuclein (h-αSyn) overexpression recapitulate some of the pathological hallmarks as it presents in humans, such as progressive cell loss and additional synucleinopathy in cortical and subcortical structures. Recent studies have combined viral vector-based overexpression of human wild-type αSyn with the sequential or simultaneous inoculation of preformed fibrils (PFFs) derived from human αSyn. Objective: The goal of the study was to investigate whether sequential or combined delivery of the AAV vector and the PFFs are equipotent in inducing stable neurodegeneration and behavioral deficits. Methods: Here we compare between four experimental paradigms (PFFs only, AAV-h-αSyn only, AAV-h-αSyn with simultaneous PFFs, and AAV-h-αSyn with sequential PFFs) and their respective GFP control groups. Results: We observed reduction of TH expression and loss of neurons in the midbrain in all AAV (h-αSyn or GFP) injected groups, with or without additional PFFs inoculation. The overexpression of either h-αSyn or GFP alone induced motor deficits and dysfunctional dopamine release/reuptake in electrochemical recordings in the ipsilateral striatum. However, we observed a substantial formation of insoluble h-αSyn aggregates and inflammatory response only when h-αSyn and PFFs were combined. Moreover, the presence of h-αSyn induced higher axonal pathology compared to control groups. Conclusion: Simultaneous AAV and PFFs injections are equipotent in the presented experimental setup in inducing histopathological and behavioral changes. This model provides new and interesting possibilities for characterizing PD pathology in preclinical models and means to assess future therapeutic interventions.
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| 4. |
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| 5. |
- Torre-Muruzabal, Teresa, et al.
(författare)
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Host oligodendrogliopathy and ɑ-synuclein strains dictate disease severity in multiple system atrophy
- 2023
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Ingår i: Brain. - : OXFORD UNIV PRESS. - 0006-8950 .- 1460-2156. ; 146:1, s. 237-251
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Tidskriftsartikel (refereegranskat)abstract
- Multiple system atrophy is a progressive neurodegenerative disease with prominent autonomic and motor features. During early stages different subtypes of multiple system atrophy are distinguished by their predominant parkinsonian or cerebellar symptoms reflecting the heterogeneous nature of the disease. The pathognomonic feature of multiple system atrophy is the presence of ɑ-synuclein (ɑSyn) protein deposits in oligodendroglial cells. ɑSyn can assemble in specific cellular or disease environments and form ɑSyn strains with unique structural features but the ability of ɑSyn strains to propagate in oligodendrocytes remains elusive. More recently, it was shown that multiple multiple system atrophy strains with related conformations exist in the brain of patients. Here, we investigated if different ɑSyn strains can influence multiple system atrophy progression in a strain-dependent manner. To this aim, we injected two recombinant ɑSyn strains (fibrils and ribbons) in multiple system atrophy transgenic mice and found that ɑSyn protein strains determine disease severity in multiple system atrophy via host-restricted and cell-specific pathology in vivo. ɑSyn strains significantly impact disease progression in a strain-dependent way via oligodendroglial, neurotoxic and immune-related mechanisms. Neurodegeneration and brain atrophy were accompanied by unique microglial and astroglial responses and the recruitment of central and peripheral immune cells. The differential activation of microglial cells correlated with the structural features of ɑSyn strains both in vitro and in vivo. Spectral analysis showed that ribbons propagate oligodendroglial inclusions that are structurally distinct from those of fibrils, with resemblance to oligodendroglial inclusions in multiple system atrophy patient brain. This study therefore shows that the multiple system atrophy phenotype is governed by both the ɑSyn strain nature and the host environment and that by injecting ɑSyn strains in a multiple system atrophy animal model a more comprehensive phenotype can be established.
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| 6. |
- Wei, Jiapeng, et al.
(författare)
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Kinetic models reveal the interplay of protein production and aggregation
- 2024
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Ingår i: Chemical Science. - 2041-6520.
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Tidskriftsartikel (refereegranskat)abstract
- Protein aggregation is a key process in the development of many neurodegenerative disorders, including dementias such as Alzheimer's disease. Significant progress has been made in understanding the molecular mechanisms of aggregate formation in pure buffer systems, much of which was enabled by the development of integrated rate laws that allowed for mechanistic analysis of aggregation kinetics. However, in order to translate these findings into disease-relevant conclusions and to make predictions about the effect of potential alterations to the aggregation reactions by the addition of putative inhibitors, the current models need to be extended to account for the altered situation encountered in living systems. In particular, in vivo, the total protein concentrations typically do not remain constant and aggregation-prone monomers are constantly being produced but also degraded by cells. Here, we build a theoretical model that explicitly takes into account monomer production, derive integrated rate laws and discuss the resulting scaling laws and limiting behaviours. We demonstrate that our models are suited for the aggregation-prone Huntington's disease-associated peptide HttQ45 utilizing a system for continuous in situ monomer production and the aggregation of the tumour suppressor protein P53. The aggregation-prone HttQ45 monomer was produced through enzymatic cleavage of a larger construct in which a fused protein domain served as an internal inhibitor. For P53, only the unfolded monomers form aggregates, making the unfolding a rate-limiting step which constitutes a source of aggregation-prone monomers. The new model opens up possibilities for a quantitative description of aggregation in living systems, allowing for example the modelling of inhibitors of aggregation in a dynamic environment of continuous protein synthesis.
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