| 1. |
- Bacelis, J., et al.
(författare)
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Decreased Risk of Parkinson's Disease after Rheumatoid Arthritis Diagnosis: A Nested Case-Control Study with Matched Cases and Controls
- 2021
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Ingår i: Journal of Parkinson's Disease. - 1877-7171 .- 1877-718X. ; 11:2, s. 821-832
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Tidskriftsartikel (refereegranskat)abstract
- Background: Rheumatoid arthritis (RA) and the genetic risk landscape of autoimmune disorders and Parkinson's disease (PD) overlap. Additionally, anti-inflammatory medications used to treat RA might influence PD risk. Objective: To use a population-based approach to determine if there is an association between pre-occurring rheumatoid arthritis (RA) and later-life risk of PD. Methods: The study population was 3.6 million residents of Sweden, who were alive during part or all of the follow-up period; 1997-2016. We obtained diagnoses from the national patient registry and identified 30,032 PD patients, 8,256 of whom each was matched to ten controls based on birth year, sex, birth location, and time of follow-up. We determined the risk reduction for PD in individuals previously diagnosed with RA. We also determined if the time (in relation to the index year) of the RA diagnosis influenced PD risk and repeated the analysis in a sex-stratified setting. Results: Individuals with a previous diagnosis of RA had a decreased risk of later developing PD by 30-50% compared to individuals without an RA diagnosis. This relationship was strongest in our conservative analysis, where the first PD diagnosis occurred close to the earliest PD symptoms (odds ratio 0.47 (CI 95% 0.28-0.75, p=0.0006); with the greatest risk reduction in females (odds ratio 0.40 (CI 95% 0,19-0.76, p=0.002). Discussion: Our findings provide evidence that individuals diagnosed with RA have a significantly lower risk of developing PD than the general population. Our data should be considered when developing or repurposing therapies aimed at modifying the course of PD. © 2021 - The authors. Published by IOS Press.
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| 2. |
- Killinger, Bryan A., et al.
(författare)
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The vermiform appendix impacts the risk of developing Parkinson’s disease
- 2018
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 10:465
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Tidskriftsartikel (refereegranskat)abstract
- The pathogenesis of Parkinson’s disease (PD) involves the accumulation of aggregated -synuclein, which has been suggested to begin in the gastrointestinal tract. Here, we determined the capacity of the appendix to modify PD risk and influence pathogenesis. In two independent epidemiological datasets, involving more than 1.6 million individuals and over 91 million person-years, we observed that removal of the appendix decades before PD onset was associated with a lower risk for PD, particularly for individuals living in rural areas, and delayed the age of PD onset. We also found that the healthy human appendix contained intraneuronal -synuclein aggregates and an abundance of PD pathology–associated -synuclein truncation products that are known to accumulate in Lewy bodies, the pathological hallmark of PD. Lysates of human appendix tissue induced the rapid cleavage and oligo-merization of full-length recombinant -synuclein. Together, we propose that the normal human appendix contains pathogenic forms of -synuclein that affect the risk of developing PD.
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| 3. |
- Smith, Ruben, et al.
(författare)
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Mutant huntingtin interacts with {beta}-tubulin and disrupts vesicular transport and insulin secretion.
- 2009
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 18:20, s. 3942-3954
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Tidskriftsartikel (refereegranskat)abstract
- Huntington's disease is a severe progressive neurodegenerative disorder caused by a CAG-expansion in the IT15 gene, which encodes huntingtin. The disease primarily affects the neostriatum and cerebral cortex and also associates with increased incidence of diabetes. Here, we show that mutant huntingtin disrupts intracellular transport and insulin secretion by direct interference with microtubular beta-tubulin. We demonstrate that mutant huntingtin impairs glucose-stimulated insulin secretion in insulin-producing beta-cells, without altering stored levels of insulin. Using VSVG-YFP, we show that mutant huntingtin retards post-Golgi transport. Moreover, we demonstrate that the speed of insulin vesicle trafficking is reduced. Using immunoprecipitation of mutant and wild-type huntingtin in combination with mass spectrometry, we reveal an enhanced and aberrant interaction between mutant huntingtin and beta-tubulin, implying the underlying mechanism of impaired intracellular transport. Thus, our findings have revealed a novel pathogenetic process by which mutant huntingtin may disrupt hormone exocytosis from beta-cells and possibly impair vesicular transport in any cell that expresses the pathogenic protein.
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| 4. |
- Ventorp, Filip, et al.
(författare)
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Exendin-4 Treatment Improves LPS-Induced Depressive-Like Behavior Without Affecting ProInflammatory Cytokines
- 2017
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Ingår i: Journal of Parkinson's Disease. - : IOS Press. - 1877-7171 .- 1877-718X. ; 7:2, s. 263-273
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Tidskriftsartikel (refereegranskat)abstract
- Background: Exendin-4 is a peptide agonist of the glucagon-like peptide-1 (GLP-1) receptor, currently in clinical trials as a potential disease-modifying therapy for Parkinson's disease. In light of this, it is important to understand potential modes of action of exendin-4 in the brain. Exendin-4 is neuroprotective and has been proposed to be directly anti-inflammatory, and that this is one way it reduces neurodegeneration. However, prior studies have focused on animal models involving both neurodegeneration and inflammation, therefore, it is also possible that the observed decreased inflammation is secondary to reduced neurodegeneration. Objective: To investigate whether exendin-4 directly reduces inflammation in the brain following an insult that involves neuroinflammation but not neurodegeneration, namely systemic administration of lipopolysaccharide (LPS). Methods: Rats were administered LPS systemically and were treated with either 0.5 mu g/kg exendin-4 or saline vehicle injections over 5 days. Behavior was evaluated with forced swim test. We assayed TNF-alpha and IL-1 beta levels in cerebrospinal fluid and cytokine mRNA expression in striatal, hippocampal and cortical tissues using qPCR. We determined brain monoamines using high-performance liquid chromatography. Finally, we isolated primary brain microglia from rats and measured cytokine production after exendin-4 treatment and LPS stimulation. Results: Exendin-4 treatment did not affect cytokine mRNA expression in brain, cytokine levels in cerebrospinal fluid or cytokine production from cultured microglia, although there was a trend towards increased striatal dopamine. Importantly, exendin-4 significantly prevented depressive-like behavior at 24 hours after LPS injection, indicating that the drug engaged a target in the brain. Depressive-like behavior was associated with altered dopamine turnover in the striatum. Conclusion: We did not detect any anti-inflammatory effects of exendin-4. In previous studies exploring the effects of exendin-4 on brain insults involving neurodegeneration, observations of reduced inflammation might have been secondary to mitigation of neuronal death. Our results indicate that the effects of exendin-4 on behavior may be due to effects on dopamine synthesis or metabolism.
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| 5. |
- Ventorp, Filip, et al.
(författare)
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The CD44 ligand hyaluronic acid is elevated in the cerebrospinal fluid of suicide attempters and is associated with increased blood-brain barrier permeability.
- 2016
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Ingår i: Journal of Affective Disorders. - : Elsevier BV. - 1573-2517 .- 0165-0327. ; 193, s. 349-354
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Tidskriftsartikel (refereegranskat)abstract
- The glycosaminoglycan hyaluronic acid (HA) is an important component of the extracellular matrix (ECM) in the brain. CD44 is a cell adhesion molecule that binds to HA in the ECM and is present on astrocytes, microglia and certain neurons. Cell adhesion molecules have been reported to be involved in anxiety and mood disorders. CD44 levels are decreased in the cerebrospinal fluid (CSF) of depressed individuals, and the CD44 gene has been identified in brain GWAS studies as a possible risk gene for suicidal behavior.
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| 6. |
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| 7. |
- Ahn, Young Hwan, et al.
(författare)
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Ultrastructural characterization of dissociated embryonic ventral mesencephalic tissue treated with neuroprotectants.
- 2003
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Ingår i: Cell Transplantation. - 1555-3892. ; 12:3, s. 235-241
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Tidskriftsartikel (refereegranskat)abstract
- Poor survival and differentiation of grafted dopamine neurons limits the application of clinical transplantation in Parkinson’s disease. The survival of grafted dopamine neurons is only improved by a factor of 2–3 by adding neuroprotectants during tissue preparation. We used dye exclusion cell viability and electron microscopy to investigate the effects of the caspase inhibitor ac-YVAD-cmk and the lazaroid tirilazad mesylate on ultrastructural changes in dissociated embryonic mesencephalic cells. In addition, we examined whether the neuroprotectants selectively counteracted specific signs of neurodegeneration. Cell viability decreased significantly over time in both control and treated cell suspensions, but the number of viable cells remaining was significantly higher in tirilazad mesylate-treated cell suspensions. In control samples, the proportion of cells with an ultrastructure consistent with healthy cells decreased from 70%, immediately after dissociation, to 30% after 8 h of incubation. Similar changes were also observed in cell suspensions treated with neuroprotectants. Thus, the neuroprotectants examined did not block the development of specific morphological signs of neurodegeneration. However, when also taking into account that dead cells lysed and disappeared from each cell suspension with time, we found that the total number of remaining viable cells with healthy nuclear chromatin or intact membrane integrity was significantly higher in the tirilazad mesylate-treated group. The results indicate that tirilazad mesylate protects only a small subpopulation of embryonic mesencephalic cells from degeneration induced by mechanical trauma during tissue dissection and dissociation.
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| 8. |
- Angot, Elodie, et al.
(författare)
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Alpha-Synuclein Cell-to-Cell Transfer and Seeding in Grafted Dopaminergic Neurons In Vivo.
- 2012
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:6
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Tidskriftsartikel (refereegranskat)abstract
- Several people with Parkinson's disease have been treated with intrastriatal grafts of fetal dopaminergic neurons. Following autopsy, 10-22 years after surgery, some of the grafted neurons contained Lewy bodies similar to those observed in the host brain. Numerous studies have attempted to explain these findings in cell and animal models. In cell culture, α-synuclein has been found to transfer from one cell to another, via mechanisms that include exosomal transport and endocytosis, and in certain cases seed aggregation in the recipient cell. In animal models, transfer of α-synuclein from host brain cells to grafted neurons has been shown, but the reported frequency of the event has been relatively low and little is known about the underlying mechanisms as well as the fate of the transferred α-synuclein. We now demonstrate frequent transfer of α-synuclein from a rat brain engineered to overexpress human α-synuclein to grafted dopaminergic neurons. Further, we show that this model can be used to explore mechanisms underlying cell-to-cell transfer of α-synuclein. Thus, we present evidence both for the involvement of endocytosis in α-synuclein uptake in vivo, and for seeding of aggregation of endogenous α-synuclein in the recipient neuron by the transferred α-synuclein. Finally, we show that, at least in a subset of the studied cells, the transmitted α-synuclein is sensitive to proteinase K. Our new model system could be used to test compounds that inhibit cell-to-cell transfer of α-synuclein and therefore might retard progression of Parkinson neuropathology.
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| 9. |
- Angot, Elodie, et al.
(författare)
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Are synucleinopathies prion-like disorders?
- 2010
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Ingår i: Lancet Neurology. - 1474-4465. ; Okt, s. 1128-1138
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Tidskriftsartikel (refereegranskat)abstract
- A shared neuropathological feature of idiopathic Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy is the development of intracellular aggregates of α-synuclein that gradually engage increasing parts of the nervous system. The pathogenetic mechanisms underlying these neurodegenerative disorders, however, are unknown. Several studies have highlighted similarities between classic prion diseases and these neurological proteinopathies. Specifically, identification of Lewy bodies in fetal mesencephalic neurons transplanted in patients with Parkinson's disease raised the hypothesis that α-synuclein, the main component of Lewy bodies, could be transmitted from the host brain to a graft of healthy neurons. These results and others have led to the hypothesis that a prion-like mechanism might underlie progression of synucleinopathy within the nervous system. We review experimental findings showing that misfolded α-synuclein can transfer between cells and, once transferred into a new cell, can act as a seed that recruits endogenous α-synuclein, leading to formation of larger aggregates. This model suggests that strategies aimed at prevention of cell-to-cell transfer of α-synuclein could retard progression of symptoms in Parkinson's disease and other synucleinopathies.
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| 10. |
- Angot, Elodie, et al.
(författare)
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Dissecting the potential molecular mechanisms underlying alpha-synuclein cell-to-cell transfer in Parkinson's disease.
- 2009
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Ingår i: Parkinsonism & Related Disorders. - 1873-5126. ; 15 Suppl 3, s. 143-147
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Tidskriftsartikel (refereegranskat)abstract
- Alpha-synuclein (alpha-syn) aggregation is central to neuropathological changes in Parkinson's disease. The aggregates spread within the central nervous system according to a very predictable pattern. A prion-like transmission of alpha-syn aggregates has been recently proposed to explain this propagation pattern. First, we review the growing evidence for such a mechanism. This process is likely to occur in three consecutive steps: (i) exit of alpha-syn template from the donor cell, (ii) entry to the recipient cell and (iii) initiation of the nucleation. In a second part, we discuss the possible underlying mechanisms for each of these steps, based on our current knowledge about how cells handle alpha-syn but also other proteins involved in neurodegenerative diseases with a prion-like propagation. Finally, we discuss which molecular species of alpha-syn (monomer, oligomer, fibril) could be the seeding-competent species and whether this seeding process could be a common mechanism in neurodegenerative diseases.
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