scholarly journals Chronic corticosterone enhancement aggravates alpha-synuclein brain spreading pathology and substantia nigra neurodegeneration in mice

2018 ◽  
Author(s):  
Johannes Burtscher ◽  
Jean-Christophe Copin ◽  
João Rodrigues ◽  
Senthil K. Thangaraj ◽  
Anass Chiki ◽  
...  
Keyword(s):  
Risk Factors ◽  
Disease Progression ◽  
Brain Regions ◽  
Alpha Synuclein ◽  
Motor Symptom ◽  
Intracerebral Injection ◽  
Lewy Pathology ◽  
Physiological Adaptations ◽  
Corticosterone Treatment ◽  
The Impact

AbstractChronic stress and associated heightened glucocorticoid levels are risk factors for depression, a common non-motor symptom in Parkinson’s disease (PD). However, how heightened glucocorticoids influence PD neuropathology [alpha-synuclein (α-Syn) containing Lewy pathology and neurodegeneration] and disease progression is unclear. To address this knowledge gap, we investigated the impact of chronic corticosterone administration on α-Syn pathology, neurodegeneration, behavior and mitochondrial function in a mouse model of α-Syn pathology spreading after intracerebral injection of α-Syn preformed fibrils (PFFs). Our results demonstrate that heightened corticosterone aggravates neurodegeneration and α-Syn pathology spreading, intriguingly to specific brain regions, such as the entorhinal cortex. Corticosterone-treatment abolished distinct physiological adaptations after PFF-injection and induced differential physiological and behavioral consequences. Taken together, our work points to elevated glucocorticoids as a risk factor for the development of the neuropathological hallmarks of PD. Strategies aimed at reducing glucocorticoid levels might slow down pathology spreading and disease progression in synucleinopathy.

scholarly journals How stress mediators can cumulatively contribute to Alzheimer’s disease An allostatic load approach

2019 ◽  
Vol 13 (1) ◽  
pp. 11-21 ◽  
Author(s):  
Tatiane Martins Matos ◽  
Juliana Nery De Souza-Talarico
Keyword(s):  
Risk Factors ◽  
Cognitive Decline ◽  
Disease Progression ◽  
Chronic Stress ◽  
Allostatic Load ◽  
Stress Hormones ◽  
Modifiable Risk Factors ◽  
Cognitive Changes ◽  
Stress Mediators ◽  
The Impact

ABSTRACT. Allostatic load is defined as the frequent activation of the neuroendocrine, immunological, metabolic and cardiovascular systems, which makes individuals more susceptible to stress-related health problems. According to this model, physiological dysregulations start to emerge decades before diseases manifest. Consequently, stress research has shifted its attention to anticipating the degree of this dysregulation to better understand the impact of stress hormones and other biomarkers on disease progression. In view of the growing number of studies that demonstrate the influence of modifiable risk factors on cognitive decline, in addition to the effects of chronic stress mediators, the objective of the present review was to present an overview of the development of cognitive changes based on studies on stress and its mediators.

scholarly journals Alpha-Synuclein: Mechanisms of Release and Pathology Progression in Synucleinopathies

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 375
Author(s):  
Inês C. Brás ◽  
Tiago F. Outeiro
Keyword(s):  
Molecular Mechanisms ◽  
Brain Regions ◽  
Alpha Synuclein ◽  
Therapeutic Strategies ◽  
Cell Protein ◽  
Protein Assemblies ◽  
Lewy Pathology ◽  
Tremendous Progress ◽  
The Brain ◽  
Made In

The accumulation of misfolded alpha-synuclein (aSyn) throughout the brain, as Lewy pathology, is a phenomenon central to Parkinson’s disease (PD) pathogenesis. The stereotypical distribution and evolution of the pathology during disease is often attributed to the cell-to-cell transmission of aSyn between interconnected brain regions. The spreading of conformationally distinct aSyn protein assemblies, commonly referred as strains, is thought to result in a variety of clinically and pathologically heterogenous diseases known as synucleinopathies. Although tremendous progress has been made in the field, the mechanisms involved in the transfer of these assemblies between interconnected neural networks and their role in driving PD progression are still unclear. Here, we present an update of the relevant discoveries supporting or challenging the prion-like spreading hypothesis. We also discuss the importance of aSyn strains in pathology progression and the various putative molecular mechanisms involved in cell-to-cell protein release. Understanding the pathways underlying aSyn propagation will contribute to determining the etiology of PD and related synucleinopathies but also assist in the development of new therapeutic strategies.

scholarly journals Neurodegeneration and neuroinflammation are linked, but independent of α-synuclein inclusions, in a seeding/spreading mouse model of Parkinson’s disease

2020 ◽  
Author(s):  
Pierre Garcia ◽  
Wiebke Jürgens-Wemheuer ◽  
Oihane Uriarte ◽  
Kristopher J Schmit ◽  
Annette Masuch ◽  
...  
Keyword(s):  
Gene Expression ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Active Role ◽  
Brain Regions ◽  
Alpha Synuclein ◽  
Intracerebral Injection ◽  
Inclusion Formation

AbstractA key process of neurodegeneration in Parkinson’s disease (PD) is the transneuronal spreading of α-synuclein. Alpha-synuclein is a presynaptic protein that is implicated in the pathogenesis of PD and other synucleinopathies, where it forms, upon intracellular aggregation, pathological inclusions. Other hallmarks of PD include neurodegeneration and microgliosis in susceptible brain regions. Whether it is primarily transneuronal spreading of α-synuclein particles, inclusion formation, or other mechanisms, such as inflammation, that cause neurodegeneration in PD is unclear. We used spreading/aggregation of α-synuclein induced by intracerebral injection of α-synuclein preformed fibrils into the mouse brain to address this question. We performed quantitative histological analysis for α-synuclein inclusions, neurodegeneration, and microgliosis in different brain regions, and a gene expression profiling of the ventral midbrain, at two different timepoints after disease induction. We observed significant neurodegeneration and microgliosis in brain regions not only with, but also without α-synuclein inclusions. We also observed prominent microgliosis in injured brain regions that did not correlate with neurodegeneration nor with inclusion load. In longitudinal gene expression profiling experiments, we observed early and unique alterations linked to microglial mediated inflammation that preceded neurodegeneration, indicating an active role of microglia in inducing neurodegeneration. Our observations indicate that α-synuclein inclusion formation is not the major driver in the early phases of PD-like neurodegeneration, but that diffusible, oligomeric α-synuclein species, which induce unusual microglial reactivity, play a key role in this process. Our findings uncover new features of α-synuclein induced pathologies, in particular microgliosis, and point to the necessity of a broader view of the process of “prion-like spreading” of that protein.

scholarly journals Inhibition of LRRK2 kinase activity promotes anterograde axonal transport and presynaptic targeting of α-synuclein

2021 ◽  
Author(s):  
Charlotte F Brzozowski ◽  
Baraa A Hijaz ◽  
Vijay Singh ◽  
Nolwazi Z Gcwensa ◽  
Kaela Kelly ◽  
...  
Keyword(s):  
Axonal Transport ◽  
Kinase Activity ◽  
Alpha Synuclein ◽  
Presynaptic Terminal ◽  
Lewy Pathology ◽  
Anterograde Axonal Transport ◽  
Lrrk2 Kinase ◽  
The Impact ◽  
Lrrk2 Kinase Activity

Pathologic inclusions composed of alpha-synuclein called Lewy pathology are hallmarks of Parkinson Disease (PD). Dominant inherited mutations in leucine rich repeat kinase 2 (LRRK2) are the most common genetic cause of PD. Lewy pathology is found in the majority of individuals with LRRK2-PD, particularly those with the G2019S-LRRK2 mutation. Lewy pathology in LRRK2-PD associates with increased non-motor symptoms such as cognitive deficits, anxiety, and orthostatic hypotension. Thus, understanding the relationship between LRRK2 and alpha-synuclein could be important for determining the mechanisms of non-motor symptoms. In PD models, expression of mutant LRRK2 reduces membrane localization of alpha-synuclein, and enhances formation of pathologic alpha-synuclein, particularly when synaptic activity is increased. alpha-Synuclein and LRRK2 both localize to the presynaptic terminal. LRRK2 plays a role in membrane traffic, including axonal transport, and therefore may influence alpha-synuclein synaptic localization. This study shows that LRRK2 kinase activity influences alpha-synuclein targeting to the presynaptic terminal. We used the selective LRRK2 kinase inhibitors, MLi-2 and PF-06685360 (PF-360) to determine the impact of reduced LRRK2 kinase activity on presynaptic localization of alpha-synuclein. Expansion microscopy (ExM) in primary hippocampal cultures and the mouse striatum, in vivo, was used to more precisely resolve the presynaptic localization of alpha-synuclein. Live imaging of axonal transport of alpha-synuclein-GFP was used to investigate the impact of LRRK2 kinase inhibition on alpha-synuclein axonal transport towards the presynaptic terminal. Reduced LRRK2 kinase activity increases alpha-synuclein overlap with presynaptic markers in primary neurons, and increases anterograde axonal transport of alpha-synuclein-GFP. In vivo, LRRK2 inhibition increases alpha-synuclein overlap with glutamatergic, cortico-striatal terminals, and dopaminergic nigral-striatal presynaptic terminals. The findings suggest that LRRK2 kinase activity plays a role in axonal transport, and presynaptic targeting of alpha-synuclein. These data provide potential mechanisms by which LRRK2-mediated perturbations of alpha-synuclein localization could cause pathology in both LRRK2-PD, and idiopathic PD.

scholarly journals Balance between transmitted HLA preadapted and nonassociated polymorphisms is a major determinant of HIV-1 disease progression

2016 ◽  
Vol 213 (10) ◽  
pp. 2049-2063 ◽  
Author(s):  
Daniela C. Mónaco ◽  
Dario A. Dilernia ◽  
Andrew Fiore-Gartland ◽  
Tianwei Yu ◽  
Jessica L. Prince ◽  
...  
Keyword(s):  
Risk Factors ◽  
Disease Progression ◽  
Major Determinant ◽  
Immune Recognition ◽  
Multivariable Model ◽  
Viral Control ◽  
New Host ◽  
Set Point ◽  
The Impact ◽  
Hiv 1

HIV-1 adapts to a new host through mutations that facilitate immune escape. Here, we evaluate the impact on viral control and disease progression of transmitted polymorphisms that were either preadapted to or nonassociated with the new host’s HLA. In a cohort of 169 Zambian heterosexual transmission pairs, we found that almost one-third of possible HLA-linked target sites in the transmitted virus Gag protein are already adapted, and that this transmitted preadaptation significantly reduced early immune recognition of epitopes. Transmitted preadapted and nonassociated polymorphisms showed opposing effects on set-point VL and the balance between the two was significantly associated with higher set-point VLs in a multivariable model including other risk factors. Transmitted preadaptation was also significantly associated with faster CD4 decline (<350 cells/µl) and this association was stronger after accounting for nonassociated polymorphisms, which were linked with slower CD4 decline. Overall, the relative ratio of the two classes of polymorphisms was found to be the major determinant of CD4 decline in a multivariable model including other risk factors. This study reveals that, even before an immune response is mounted in the new host, the balance of these opposing factors can significantly influence the outcome of HIV-1 infection.

scholarly journals Neurodegeneration and Neuroinflammation are Linked, but Independent of α-Synuclein Inclusions, in a Seeding/Spreading Mouse Model of Parkinson’s Disease

2020 ◽  
Author(s):  
Pierre Garcia ◽  
Wiebke Wemheuer ◽  
Oihane Uriarte ◽  
Kristopher J Schmit ◽  
Annette Masuch ◽  
...  
Keyword(s):  
Gene Expression ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Active Role ◽  
Brain Regions ◽  
Alpha Synuclein ◽  
Intracerebral Injection ◽  
Inclusion Formation

Abstract Background: Akey process of neurodegeneration in Parkinson’s disease (PD) is the transneuronal spreading of a-synuclein. Alpha-synuclein is a presynaptic protein that is implicated in the pathogenesis of PD and other synucleinopathies, where it forms, upon intracellular aggregation, pathological inclusions.Other hallmarks of PD include neurodegeneration and microgliosis in susceptible brain regions. Whether it is primarilytransneuronal spreading of a-synuclein particles,inclusion formation, or other mechanisms, such as inflammation,that cause neurodegeneration in PDis unclear.Methods: We used spreading/aggregation ofa-synuclein induced by intracerebral injection of a-synucleinpreformed fibrils into the mouse brain to address this question. We performed quantitative histological analysis for a-synuclein inclusions, neurodegeneration, and microgliosis in different brain regions, and a gene expression profiling of the ventral midbrain, at two different timepoints after disease induction.Results: We observed significant neurodegeneration and microgliosis in brain regions not only with,but alsowithouta-synuclein inclusions. We also observed prominent microgliosis in injured brain regions that did not correlate with neurodegeneration nor with inclusion load. In longitudinal gene expression profiling experiments, we observedearly and unique alterationslinkedto microglial mediated inflammation that preceded neurodegeneration, indicating an active role of microglia in inducing neurodegeneration. Our observations indicate that a-synuclein inclusion formation is not the major driverin the early phases of PD-like neurodegeneration, but that diffusible, oligomeric a-synuclein species,which induce unusual microglial reactivity, play a key role in this process.Conclusion: Our findings uncover new features of a-synuclein induced pathologies, in particular microgliosis, and point to the necessity of a broader view of the process of “prion-like spreading” of that protein.

scholarly journals 14-3-3 mitigates alpha-synuclein aggregation and toxicity in the in vivo preformed fibril model

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Rachel Underwood ◽  
Mary Gannon ◽  
Aneesh Pathak ◽  
Navya Kapa ◽  
Sidhanth Chandra ◽  
...  
Keyword(s):  
Social Dominance ◽  
Lewy Bodies ◽  
Brain Regions ◽  
Alpha Synuclein ◽  
Transgenic Expression ◽  
Dopaminergic Cells ◽  
Cell Internalization ◽  
The Impact

AbstractAlpha-synuclein (αsyn) is the key component of proteinaceous aggregates termed Lewy Bodies that pathologically define a group of disorders known as synucleinopathies, including Parkinson’s Disease (PD) and Dementia with Lewy Bodies. αSyn is hypothesized to misfold and spread throughout the brain in a prion-like fashion. Transmission of αsyn necessitates the release of misfolded αsyn from one cell and the uptake of that αsyn by another, in which it can template the misfolding of endogenous αsyn upon cell internalization. 14-3-3 proteins are a family of highly expressed brain proteins that are neuroprotective in multiple PD models. We have previously shown that 14-3-3θ acts as a chaperone to reduce αsyn aggregation, cell-to-cell transmission, and neurotoxicity in the in vitro pre-formed fibril (PFF) model. In this study, we expanded our studies to test the impact of 14-3-3s on αsyn toxicity in the in vivo αsyn PFF model. We used both transgenic expression models and adenovirus associated virus (AAV)-mediated expression to examine whether 14-3-3 manipulation impacts behavioral deficits, αsyn aggregation, and neuronal counts in the PFF model. 14-3-3θ transgene overexpression in cortical and amygdala regions rescued social dominance deficits induced by PFFs at 6 months post injection, whereas 14-3-3 inhibition by transgene expression of the competitive 14-3-3 peptide inhibitor difopein in the cortex and amygdala accelerated social dominance deficits. The behavioral rescue by 14-3-3θ overexpression was associated with delayed αsyn aggregation induced by PFFs in these brain regions. Conversely, 14-3-3 inhibition by difopein in the cortex and amygdala accelerated αsyn aggregation and reduction in NECAB1-positive neuron counts induced by PFFs. 14-3-3θ overexpression by AAV in the substantia nigra (SN) also delayed αsyn aggregation in the SN and partially rescued PFF-induced reduction in tyrosine hydroxylase (TH)-positive dopaminergic cells in the SN. 14-3-3 inhibition in the SN accelerated nigral αsyn aggregation and enhanced PFF-induced reduction in TH-positive dopaminergic cells. These data indicate a neuroprotective role for 14-3-3θ against αsyn toxicity in vivo.

scholarly journals 14-3-3 mitigates alpha-synuclein aggregation and toxicity in the in vivo preformed fibril model

2020 ◽  
Author(s):  
Rachel Underwood ◽  
Mary Gannon ◽  
Aneesh Pathak ◽  
Navya Kapa ◽  
Sidhanth Chandra ◽  
...  
Keyword(s):  
Social Dominance ◽  
Lewy Bodies ◽  
Neuronal Loss ◽  
Cell Loss ◽  
Brain Regions ◽  
Alpha Synuclein ◽  
Dopaminergic Cell ◽  
The Impact

AbstractAlpha-synuclein (αsyn) is the key component of proteinaceous aggregates termed Lewy Bodies (LBs) that pathologically define a group of disorders known as synucleinopathies, including Parkinson’s Disease (PD) and Dementia with Lewy Bodies (DLB). αSyn is hypothesized to misfold and spread throughout the brain in a prion-like fashion. Transmission of αsyn necessitates the release of misfolded αsyn from one cell and the uptake of that αsyn by another, in which it can template the misfolding of endogenous αsyn upon cell internalization. 14-3-3 proteins are a family of highly expressed brain proteins that are neuroprotective in multiple PD models. We have previously shown that 14-3-3θ acts as a chaperone to reduce αsyn aggregation, cell-to-cell transmission, and neurotoxicity in the in vitro pre-formed fibril (PFF) model. In this study, we expanded our studies to test the impact of 14-3-3s on αsyn toxicity in the in vivo αsyn PFF model. We used both transgenic expression models and adenovirus associated virus (AAV)-mediated expression to examine whether 14-3-3 manipulation impacts behavioral deficits, αsyn aggregation, and neuronal loss in the PFF model. 14-3-3θ transgene overexpression in cortical and amygdala regions rescued social dominance deficits induced by PFFs at 6 months post injection, whereas 14-3-3 inhibition by transgene expression of the competitive 14-3-3 peptide inhibitor difopein in the cortex and amygdala accelerated social dominance deficits. The behavioral rescue by 14-3-3θ overexpression was associated with delayed αsyn aggregation induced by PFFs in these brain regions. Conversely, 14-3-3 inhibition by difopein in the cortex and amygdala accelerated αsyn aggregation and cortical pyramidal neuron loss induced by PFFs. 14-3-3θ overexpression by AAV in the substantia nigra (SN) also delayed αsyn aggregation in the SN and partially rescued PFF-induced dopaminergic cell loss in the SN. 14-3-3 inhibition in the SN accelerated nigral αsyn aggregation and increased PFF-induced dopaminergic cell loss. These data indicate a neuroprotective role for 14-3-3θ against αsyn toxicity in vivo.

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