The pathogenesis of Parkinson's disease

The Lancet, Год журнала: 2024, Номер 403(10423), С. 293 - 304

Опубликована: Янв. 1, 2024

Язык: Английский

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The role of inflammasomes in human diseases and their potential as therapeutic targets

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Янв. 5, 2024

Abstract Inflammasomes are large protein complexes that play a major role in sensing inflammatory signals and triggering the innate immune response. Each inflammasome complex has three components: an upstream sensor molecule is connected to downstream effector such as caspase-1 through adapter ASC. Inflammasome formation typically occurs response infectious agents or cellular damage. The active then triggers activation, followed by secretion of pro-inflammatory cytokines pyroptotic cell death. Aberrant activation activity contribute development diabetes, cancer, several cardiovascular neurodegenerative disorders. As result, recent research increasingly focused on investigating mechanisms regulate assembly well potential targeting inflammasomes treat various diseases. Multiple clinical trials currently underway evaluate therapeutic distinct inflammasome-targeting therapies. Therefore, understanding how different disease pathology may have significant implications for developing novel strategies. In this article, we provide summary biological pathological roles health disease. We also highlight key evidence suggests could be strategy new disease-modifying therapies effective conditions.

Язык: Английский

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A systematic review and meta-analysis of inflammatory biomarkers in Parkinson’s disease

npj Parkinson s Disease, Год журнала: 2023, Номер 9(1)

Опубликована: Фев. 4, 2023

Abstract Neuroinflammation plays a crucial role in the pathogenesis of Parkinson’s disease (PD), but controversies persist. Studies reporting concentrations blood or cerebrospinal fluid (CSF) markers for patients with PD and controls were included extracted. Pooled Hedges’g was adopted to illustrate comparisons, covariates used explore sources heterogeneity. Finally, 152 studies included. Increased IL-6, TNF-α, IL-1β, STNFR1, CRP, CCL2, CX3CL1, CXCL12 levels decreased INF-γ IL-4 noted group. In addition, increased CSF CRP CCL2 revealed compared controls. Consequently, significantly altered inflammatory verified between group control, suggesting that is accompanied by responses both peripheral CSF. This study registered PROSPERO, CRD42022349182.

Язык: Английский

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Innate immune activation in neurodegenerative diseases

Immunity, Год журнала: 2024, Номер 57(4), С. 790 - 814

Опубликована: Апрель 1, 2024

Язык: Английский

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Monocyte-derived cells invade brain parenchyma and amyloid plaques in human Alzheimer’s disease hippocampus

Acta Neuropathologica Communications, Год журнала: 2023, Номер 11(1)

Опубликована: Фев. 28, 2023

Microglia are brain-resident myeloid cells and play a major role in the innate immune responses of CNS pathogenesis Alzheimer's disease (AD). However, contribution nonparenchymal or brain-infiltrated to progression remains be demonstrated. Here, we show that monocyte-derived (MDC) invade brain parenchyma advanced stages AD continuum using transcriptional analysis immunohistochemical characterization post-mortem human hippocampus. Our findings demonstrated high proportion (60%) demented Braak V-VI individuals was associated with up-regulation genes rarely expressed by microglial abundant monocytes, among which stands membrane-bound scavenger receptor for haptoglobin/hemoglobin complexes Cd163. These Cd163-positive MDC invaded hippocampal parenchyma, acquired microglial-like morphology, were located close proximity blood vessels. Moreover, most interesting, these invading monocytes infiltrated nearby amyloid plaques contributing plaque-associated cell heterogeneity. aged-matched control pathology, no signs infiltration plaque invasion found. The previously reported degeneration/dysfunction hippocampus could key pathological factor inducing recruitment. data suggest clear association between endothelial activation turn may contribute damage barrier integrity. recruitment consequence rather than cause severity disease. Whether monocyte is beneficial detrimental pathology fully elucidated. open opportunity design targeted therapies, not only microglia but also peripheral population modulate provide better understanding immunological mechanisms underlying AD.

Язык: Английский

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The systemic immune response in Parkinson’s disease: focus on the peripheral immune component

Trends in Neurosciences, Год журнала: 2023, Номер 46(10), С. 863 - 878

Опубликована: Авг. 17, 2023

Язык: Английский

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Immunological shifts during early-stage Parkinson’s disease identified with DNA methylation data on longitudinally collected blood samples

npj Parkinson s Disease, Год журнала: 2024, Номер 10(1)

Опубликована: Янв. 11, 2024

Abstract Parkinson’s disease (PD) is the second most common neurodegenerative in United States. Decades before motor symptoms manifest, non-motor such as hyposmia and rapid eye movement (REM) sleep behavior disorder are highly predictive of PD. Previous immune profiling studies have identified alterations to proportions cells blood clinically defined PD patients. However, it remains unclear if these phenotypes manifest clinical diagnosis We utilized longitudinal DNA methylation (DNAm) microarray data from Progression Marker’s Initiative (PPMI) perform prodromal patients (Prod). previously reported changes neutrophil, monocyte, T cell numbers Additionally, we noted unrecognized decreases naive B compartment Prod patient group. Over time, observed proportion innate increased, but adaptive decreased. subsets associated with REM disturbances early cognitive decline. Lastly, increases memory both genetic ( LRRK2 genotype) infectious (cytomegalovirus seropositivity) risk factors Our analysis shows that peripheral system dynamic progresses. The study provides a platform understand how when occur whether intervention at particular stages may be therapeutically advantageous.

Язык: Английский

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Neuroinflammation and Immune Changes in Prodromal Parkinson’s Disease and Other Synucleinopathies

Journal of Parkinson s Disease, Год журнала: 2022, Номер 12(s1), С. S149 - S163

Опубликована: Июнь 14, 2022

Multiple lines of clinical and pre-clinical research support a pathogenic role for neuroinflammation peripheral immune system dysfunction in Parkinson's disease. In this paper, we have reviewed summarised the published literature reporting evidence changes cohorts patients with isolated REM sleep behaviour disorder non-manifesting carriers GBA or LRRK2 gene mutations, who increased risk Parkinsonism synucleinopathies, could be prodromal stage these conditions. Taken together, findings studies suggest that early stages pathology involve activation both central systems significant crosstalk. We consider respect to those found disease discuss their possible pathological roles. Moreover, factors possibly associated response, such as immunomodulatory affected neurotransmitters gut-brain axis, are also considered.

Язык: Английский

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Sex differences in alpha-synucleinopathies: a systematic review

Frontiers in Neurology, Год журнала: 2023, Номер 14

Опубликована: Июль 20, 2023

Past research indicates a higher prevalence, incidence, and severe clinical manifestations of alpha-synucleinopathies in men, leading to suggestion neuroprotective properties female sex hormones (especially estrogen). The potential pathomechanisms any such effect on alpha-synucleinopathies, however, are far from understood. With that aim, we undertook systematically review, critically assess, contemporary evidence gender differences using bench-to-bedside approach.In this systematic studies investigating (Rapid Eye Movement (REM) Behavior Disorder (RBD), Parkinson's Disease (PD), Dementia with Lewy Bodies (DLB), Multiple System Atrophy (MSA)) 2012 2022 were identified electronic database searches PubMed, Embase Ovid.One hundred sixty-two included; 5 RBD, 6 MSA, 20 DLB 131 PD studies. Overall, there is conclusive suggest sex-and gender-specific manifestation demographics, biomarkers, genetics, features, interventions, quality life alpha-synucleinopathies. Only limited data exists the effects distinct hormones, majority concentrating estrogen its speculated effects.Future disentangling underlying sex-specific mechanisms urgently needed order enable novel therapeutics.

Язык: Английский

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The major histocompatibility complex participates in Parkinson’s disease

Pharmacological Research, Год журнала: 2024, Номер 203, С. 107168 - 107168

Опубликована: Апрель 5, 2024

Parkinson's disease (PD) is a common neurodegenerative characterized by progressive loss of dopaminergic neurons in the substantia nigra and aggregation alpha-synuclein (α-syn). The central nervous system (CNS) has previously been considered as an immune-privileged area. However, studies have shown that immune responses are involved PD. major histocompatibility complex (MHC) presents antigens from Antigen-presenting cells(APCs) to T lymphocytes, will be induced. MHCs expressed microglia, astrocytes, neurons. Single nucleotide polymorphisms MHC related risk aggregated α-syn triggers expression activating glia cells. CD4+ CD8+ lymphocytes microglia activation detected brains PD patients. In addiction further increase blood-brain barrier (BBB) permeability cell infiltration Thus, through participating inflammatory responses.

Язык: Английский

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