Inflammation and immune dysfunction in Parkinson disease

Nature reviews. Immunology, Journal Year: 2022, Volume and Issue: 22(11), P. 657 - 673

Published: March 4, 2022

Language: Английский

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Inflammation in Parkinson’s Disease: Mechanisms and Therapeutic Implications

Cells, Journal Year: 2020, Volume and Issue: 9(7), P. 1687 - 1687

Published: July 14, 2020

Parkinson’s disease (PD) is a common neurodegenerative disorder primarily characterized by the death of dopaminergic neurons that project from substantia nigra pars compacta. Although molecular bases for PD development are still little defined, extensive evidence human samples and animal models support involvement inflammation in onset or progression. However, exact trigger this response remains unclear. Here, we provide systematic review cellular mediators, i.e., microglia, astroglia endothelial cells. We also discuss genetic transcriptional control immunomodulatory role dopamine reactive oxygen species. Finally, summarize preclinical clinical approaches targeting neuroinflammation PD.

Language: Английский

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Modeling Parkinson’s Disease With the Alpha-Synuclein Protein

Frontiers in Pharmacology, Journal Year: 2020, Volume and Issue: 11

Published: April 23, 2020

Alpha-synuclein (α-Syn) is a key protein involved in Parkinson's disease (PD) pathology. PD characterized by the loss of dopaminergic neuronal cells substantia nigra pars compacta and abnormal accumulation aggregation α-Syn form Lewy bodies neurites. More precisely, associated with dysfunctionality degeneration neurons PD. Moreover, mutations SNCA gene, which encodes α-Syn, cause familial forms are basis sporadic risk. Given role pathology PD, animal models that reflect widespread progressive formation aggregates different areas brain constitute valuable tool. Indeed, important for understanding molecular mechanisms might contribute to development validation new therapies. In absence faithfully reproduce human recent years, numerous based on have been generated. this review, we summarize main features pre-formed fibrils (PFFs) model recombinant adeno-associated virus vector (rAAV) mediated overexpression models, providing detailed comparative analysis both models. Here, discuss how each has contributed our advantages weakness them.Here, show injection PFFs rAAV lead pattern rodents. First, trigger body-like inclusions regions directly interconnected site, suggesting there an inter-neuronal transmission contrast, rAAV-mediated limits within transduced neurons. Second, phosphorylated obtained predominantly nuclear punctate appearance becomes diffuse along fibers, whereas cytoplasmic reminiscent

Language: Английский

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CD4 T cells mediate brain inflammation and neurodegeneration in a mouse model of Parkinson's disease

Brain, Journal Year: 2021, Volume and Issue: 144(7), P. 2047 - 2059

Published: March 8, 2021

α-Synuclein, a key pathological component of Parkinson's disease, has been implicated in the activation innate and adaptive immune system. This includes microgliosis, increased inflammatory cytokines, infiltration T cells into CNS. More recently, peripherally circulating CD4 CD8 derived from individuals with disease have shown to produce Th1/Th2 cytokines response α-synuclein, suggesting there may be chronic memory cell present disease. To understand potential effects these α-syn associated responses we used an α-synuclein overexpression mouse model, cell-deficient mice, combination immunohistochemistry flow cytometry. In this study, found that midbrain mice leads upregulation major histocompatibility complex II (MHCII) protein on CNS myeloid as well IFNγ producing Interestingly, genetic deletion TCRβ or CD4, use immunosuppressive drug fingolimod, were able reduce MHCII α-synuclein. Furthermore, observed CD4-deficient protected dopaminergic loss due overexpression. These results suggest pathology damaging areas targeting could avenue for modifying treatments.

Language: Английский

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Periphery and brain, innate and adaptive immunity in Parkinson’s disease

Acta Neuropathologica, Journal Year: 2021, Volume and Issue: 141(4), P. 527 - 545

Published: Feb. 8, 2021

Abstract Parkinson’s disease (PD) is a neurodegenerative disorder where alpha-synuclein plays central role in the death and dysfunction of neurons, both, central, as well peripheral nervous system. Besides neuronal events observed patients, PD also includes significant immune component. It suggested that PD-associated response will have consequences on health, thus opening immunomodulation potential therapeutic strategy PD. The changes during occur brain, involving microglia, but periphery with cells innate system, particularly monocytes, those adaptive immunity, such T-cells. This realization arises from multiple patient studies, data animal models disease, providing strong evidence for system crosstalk Here we review showing crucial activation We describe studies suggesting inflammation early develop dynamically through time contributing to degeneration symptomatology patients. novel finding has contributed definition multisystem should be approached more integratory manner rather than brain-focused classical approach.

Language: Английский

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Signaling pathways in Parkinson’s disease: molecular mechanisms and therapeutic interventions

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Feb. 21, 2023

Abstract Parkinson’s disease (PD) is the second most common neurodegenerative worldwide, and its treatment remains a big challenge. The pathogenesis of PD may be related to environmental genetic factors, exposure toxins gene mutations beginning brain lesions. identified mechanisms include α-synuclein aggregation, oxidative stress, ferroptosis, mitochondrial dysfunction, neuroinflammation, gut dysbiosis. interactions among these molecular complicate pose great challenges drug development. At same time, diagnosis detection are also one obstacles due long latency complex mechanism. Most conventional therapeutic interventions for possess limited effects have serious side effects, heightening need develop novel treatments this disease. In review, we systematically summarized pathogenesis, especially PD, classical research models, clinical diagnostic criteria, reported therapy strategies, as well newly candidates in trials. We shed light on components derived from medicinal plants that their treatment, with expectation provide summary outlook developing next generation drugs preparations therapy.

Language: Английский

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Neuroimaging evidence of glymphatic system dysfunction in possible REM sleep behavior disorder and Parkinson’s disease

npj Parkinson s Disease, Journal Year: 2022, Volume and Issue: 8(1)

Published: April 29, 2022

Alpha-synucleinopathy is postulated to be central both idiopathic rapid eye movement sleep behaviour disorder (iRBD) and Parkinson's disease (PD). Growing evidence suggests an association between the diminished clearance of α-synuclein glymphatic system dysfunction. However, accumulating primarily based on clinical data support dysfunction in patients with iRBD PD currently insufficient. This study aimed use diffusion tensor image analysis along perivascular space (DTI-ALPS) evaluate activity its relationship scores severity possible (piRBDs) those PD. Further, we validated correlation ALPS index prognosis longitudinally. Overall, 168 PD, 119 piRBDs, 129 healthy controls were enroled. Among them, 50 had been longitudinally reexamined. Patients exhibited a lower than piRBDs (P = 0.036), patient groups showed < 0.001 P 0.001). The elevated negatively correlated piRBD subgroups. Moreover, was cognitive decline longitudinal analyses. In conclusion, DTI-ALPS provided neuroimaging PD; however, potential assessing pathological progress α-synucleinopathies as indicator worth verifying. Further development imaging methods for function also warranted.

Language: Английский

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Advances in understanding the function of alpha-synuclein: implications for Parkinson’s disease

Brain, Journal Year: 2023, Volume and Issue: 146(9), P. 3587 - 3597

Published: May 15, 2023

The critical role of alpha-synuclein in Parkinson's disease represents a pivotal discovery. Some progress has been made over recent years identifying disease-modifying therapies for that target alpha-synuclein. However, these treatments have not yet shown clear efficacy slowing the progression this disease. Several explanations exist issue. pathogenesis is complex and fully clarified heterogeneity disease, with diverse genetic susceptibility risk factors different clinical courses, adds further complexity. Thus, deep understanding physiological pathophysiological functions crucial. In review, we first describe cellular animal models developed to study pathological roles protein, including transgenic techniques, use viral vectors intracerebral injections fibrils. We then provide evidence tools are crucial modelling pathogenesis, causing protein misfolding aggregation, synaptic dysfunction, brain plasticity impairment cell-to-cell spreading species. particular, focus on possibility dissecting pre- postsynaptic effects both conditions. Finally, show how vulnerability specific neuronal cell types may facilitate systemic dysfunctions leading multiple network alterations. These functional alterations underlie motor non-motor manifestations occur before overt neurodegeneration. now understand therapeutic targeting patients requires caution, since exerts important functions. Moreover, interactions other molecules induce synergistic detrimental effects. only might be enough. Combined should considered future.

Language: Английский

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Animal models of Parkinson’s disease: bridging the gap between disease hallmarks and research questions

Translational Neurodegeneration, Journal Year: 2023, Volume and Issue: 12(1)

Published: July 19, 2023

Abstract Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms. More than 200 years after its first clinical description, PD remains serious affliction that affects growing proportion of the population. Prevailing treatments only alleviate symptoms; there still neither cure targets processes nor therapies modify course disease. Over past decades, several animal models have been developed to study PD. Although no model precisely recapitulates pathology, they provide valuable information contributes our understanding limitations treatment options. This review comprehensively summarizes different available for research, with focus on those induced drugs, neurotoxins, pesticides, genetic alterations, α-synuclein inoculation, viral vector injections. We highlight their characteristics ability reproduce PD-like phenotypes. It essential realize strengths weaknesses each induction technique at disposal are determined research question being asked. Our review, therefore, seeks better aid researchers ensuring concrete discernment classical novel in research.

Language: Английский

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The immune system in Parkinson’s disease: what we know so far

Brain, Journal Year: 2024, Volume and Issue: unknown

Published: June 3, 2024

Abstract Parkinson's disease (PD) is characterised neuropathologically by the degeneration of dopaminergic neurons in ventral midbrain, accumulation α-synuclein (α-syn) aggregates neurons, and chronic neuroinflammation. In past two decades, vitro, ex vivo studies have consistently shown involvement inflammatory responses mediated microglia astrocytes, which may be elicited pathological α-syn or signals from affected other cell types, are directly linked to neurodegeneration development. Besides prominent immune alterations seen central nervous system (CNS), including infiltration T-cells into brain, more recent demonstrated important changes peripheral profile within both innate adaptive compartments, particularly involving monocytes, CD4+ CD8+ T-cells. This review aims integrate consolidated understanding immune-related processes underlying pathogenesis PD, focusing on cells, neuron-glia crosstalk as well central-peripheral interaction during development PD. Our analysis seeks provide a comprehensive view emerging knowledge mechanisms immunity PD implications this for better overall disease.

Language: Английский

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