The pathogenesis of Parkinson's disease

The Lancet, Journal Year: 2024, Volume and Issue: 403(10423), P. 293 - 304

Published: Jan. 1, 2024

Language: Английский

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An AAV capsid reprogrammed to bind human transferrin receptor mediates brain-wide gene delivery

Science, Journal Year: 2024, Volume and Issue: 384(6701), P. 1220 - 1227

Published: May 16, 2024

Developing vehicles that efficiently deliver genes throughout the human central nervous system (CNS) will broaden range of treatable genetic diseases. We engineered an adeno-associated virus (AAV) capsid, BI-hTFR1, binds transferrin receptor (TfR1), a protein expressed on blood-brain barrier. BI-hTFR1 was actively transported across brain endothelial cells and, relative to AAV9, provided 40 50 times greater reporter expression in CNS

Language: Английский

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Akkermansia muciniphila in neuropsychiatric disorders: friend or foe?

Frontiers in Cellular and Infection Microbiology, Journal Year: 2023, Volume and Issue: 13

Published: July 10, 2023

An accumulating body of evidence suggests that the bacterium Akkermansia muciniphila exhibits positive systemic effects on host health, mainly by improving immunological and metabolic functions, it is therefore regarded as a promising potential probiotic. Recent clinical preclinical studies have shown A. plays vital role in variety neuropsychiatric disorders influencing brain through microbiota-gut-brain axis (MGBA). Numerous observed its substances can effectively improve symptoms restoring gut microbiota, reestablishing integrity mucosal barrier, regulating immunity, modulating neuroinflammation. However, was also reported to participate development aggravating inflammation mucus production. Therefore, exact mechanism action remains much controversial. This review summarizes proposed roles mechanisms various neurological psychiatric such depression, anxiety, Parkinson’s disease, Alzheimer’s multiple sclerosis, strokes, autism spectrum disorders, provides insights into therapeutic application for treatment these conditions.

Language: Английский

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New insight on the possible role of statins in Vascular Parkinsonism: A need for presumptive therapy

Ageing Research Reviews, Journal Year: 2024, Volume and Issue: 95, P. 102209 - 102209

Published: Jan. 28, 2024

Language: Английский

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Towards a Global View of Parkinson's Disease Genetics

Annals of Neurology, Journal Year: 2024, Volume and Issue: 95(5), P. 831 - 842

Published: April 1, 2024

Parkinson's disease (PD) is a global health challenge, yet historically studies of PD have taken place predominantly in European populations. Recent genetics research conducted non-European populations has revealed novel population-specific genetic loci linked to risk, highlighting the importance studying globally. These insights broadened our understanding etiology, which crucial for developing disease-modifying interventions. This review comprehensively explores landscape PD, emphasizing scientific rationale underrepresented It underscores challenges, such as genotype-phenotype heterogeneity and inclusion difficulties participants, ongoing need diverse inclusive PD. ANN NEUROL 2024;95:831-842.

Language: Английский

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Peripheral inflammatory immune response differs among sporadic and familial Parkinson’s disease

npj Parkinson s Disease, Journal Year: 2023, Volume and Issue: 9(1)

Published: Jan. 31, 2023

Abstract Peripheral inflammatory immune responses are thought to play a major role in the pathogenesis of Parkinson’s disease (PD). The neutrophil-to-lymphocyte ratio (NLR), biomarker systemic inflammation, has been reported be higher patients with PD than healthy controls (HCs). present study was aimed at determining if peripheral response could influenced by genetic background PD. We included discovery cohort 222 (132 sporadic PD, 44 LRRK2 -associated (with p.G2019S and p.R1441G variants), 46 GBA PD), as well 299 HCs. Demographic clinical data were recorded. Leukocytes their subpopulations, NLR measured blood. Multivariate lineal regression post-hoc tests applied determine differences among groups. Subsequently, replication using Progression Markers Initiative performed which 401 (281 sPD patients, 66 -PD 54 patients) group 174 Patients showed significantly lower lymphocyte count, non-significantly neutrophil count did not differ from Our supports involvement pathophysiology However, this found probably reflecting different pathogenic mechanisms.

Language: Английский

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Neuroinflammation is linked to dementia risk in Parkinson’s disease

Brain, Journal Year: 2023, Volume and Issue: 147(3), P. 923 - 935

Published: Sept. 27, 2023

Abstract The development of dementia is a devastating aspect Parkinson’s disease (PD), affecting nearly half patients within 10 years post-diagnosis. For effective therapies to prevent and slow progression PD (PDD), the key mechanisms that determine why some people with develop early dementia, while others remain cognitively unaffected, need be understood. Neuroinflammation tau protein accumulation have been demonstrated in post-mortem brains, many other neurodegenerative disorders leading dementia. However, whether these processes mediate risk on course not established. To this end, we used PET neuroimaging 11C-PK11195 index neuroinflammation 18F-AV-1451 for misfolded patients, stratified according our ‘Neuroinflammation Tau Accumulation Disease Dementia’ (NET-PDD) study. NET-PDD study longitudinally assesses newly-diagnosed two subgroups at low high (stratified based pentagon copying, semantic fluency, MAPT genotype), comparison age- sex-matched controls. Non-displaceable binding potential (BPND) 43 brain regions (Hammers’ parcellation) was compared between groups (pairwise t-tests), associations BPND tracers tested (linear-mixed-effect models). We hypothesized higher greater inflammation and/or advance significant cognitive decline. found significantly elevated (11C-PK11195 BPND) multiple subcortical restricted cortical group controls, low-risk limited areas. also showed than concentrated basal ganglia regions. most associated worse performance (Addenbrooke’s Cognitive Examination-III score). Overall burden correlated serum levels pro-inflammatory cytokines. In contrast, increases (tau) versus controls were where off-target typically seen, no relationship cognition found. Whole-brain phosphorylated tau181 levels. Although there minimal regional PD, participants, strongest association group, suggesting possible co-localization pathologies. conclusion, findings suggest might underpin PDD development, indicating as putative modifiable aetiopathological factor or using immunomodulatory strategies.

Language: Английский

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The Consequences of GBA Deficiency in the Autophagy–Lysosome System in Parkinson’s Disease Associated with GBA

Cells, Journal Year: 2023, Volume and Issue: 12(1), P. 191 - 191

Published: Jan. 3, 2023

GBA gene variants were the first genetic risk factor for Parkinson’s disease. encodes lysosomal enzyme glucocerebrosidase (GBA), which is involved in sphingolipid metabolism. exhibits a complex physiological function that includes not only degradation of its substrate glucosylceramide but also metabolism other sphingolipids and additional lipids such as cholesterol, particularly when activity deficient. In context disease associated with GBA, loss has been accumulation α-synuclein species. recent years, several hypotheses have proposed alternative complementary pathological mechanisms to explain why mutations lead become important factors etiology. Classically, linked dysfunctional autophagy–lysosome system subsequent decrease autophagy-dependent turnover; however, underlying GBA-associated parkinsonism proposed. This review summarizes discusses different special focus on mechanisms, well autophagy-independent where role players sphingolipids, cholesterol GBA-related proteins make contributions pathogenesis.

Language: Английский

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GBA1 Gene Mutations in α-Synucleinopathies—Molecular Mechanisms Underlying Pathology and Their Clinical Significance

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(3), P. 2044 - 2044

Published: Jan. 20, 2023

α-Synucleinopathies comprise a group of neurodegenerative diseases characterized by altered accumulation protein called α-synuclein inside neurons and glial cells. This aggregation leads to the formation intraneuronal inclusions, Lewy bodies, that constitute hallmark pathology. The most prevalent α-synucleinopathies are Parkinson’s disease (PD), dementia with bodies (DLB), multiple system atrophy (MSA). To date, only symptomatic treatment is available for these disorders, hence new approaches their therapy needed. It has been observed GBA1 mutations one impactful risk factors developing such as PD DLB. Mutations in gene, which encodes lysosomal hydrolase β-glucocerebrosidase (GCase), cause reduction GCase activity impaired metabolism. abundant gene N370S or N409S, L444P/L483P E326K/E365K. mechanisms impacts poorly understood need be further investigated. Here, we discuss some potential interactions between show how may impact course α-synucleinopathies.

Language: Английский

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Untargeted serum metabolomics reveals novel metabolite associations and disruptions in amino acid and lipid metabolism in Parkinson’s disease

Molecular Neurodegeneration, Journal Year: 2023, Volume and Issue: 18(1)

Published: Dec. 19, 2023

Abstract Background Untargeted high-resolution metabolomic profiling provides simultaneous measurement of thousands metabolites. Metabolic networks based on these data can help uncover disease-related perturbations across interconnected pathways. Objective Identify metabolic disturbances associated with Parkinson’s disease (PD) in two population-based studies using untargeted metabolomics. Methods We performed a metabolome-wide association study (MWAS) PD serum-based metabolomics derived from liquid chromatography mass spectrometry (LC-HRMS) distinct case-control populations. also combined our results previous publication 34 metabolites linked to large-scale, MWAS assess external validation. Results LC-HRMS detected 4,762 for analysis (HILIC: 2716 metabolites; C18: 2046 metabolites). identified 296 features at FDR<0.05, 134 having log 2 fold change (FC) beyond ±0.5 (228 ±0.25). Of these, 104 were independently both discovery and replication p <0.05 (170 <0.10), while 27 levodopa-equivalent dose among the patients. Intriguingly, externally validated microbial-related metabolites, p-cresol glucuronide (FC=2.52, 95% CI=1.67, 3.81, FDR=7.8e-04) sulfate. P-cresol was motor symptoms Additional include phenylacetyl-L-glutamine, trigonelline, kynurenine, biliverdin, pantothenic acid. Novel associations anti-inflammatory metabolite itaconate (FC=0.79, CI=0.73, 0.86; FDR=2.17E-06) cysteine-S-sulfate (FC=1.56, CI=1.39, 1.75; FDR=3.43E-11). Seventeen pathways enriched, including several related amino acid lipid metabolism. Conclusions Our revealed PD-associated confirming observations, glucuronide, newly implicating interesting such as itaconate. suggests metabolism inflammatory processes PD.

Language: Английский

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