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

Science, Год журнала: 2024, Номер 384(6701), С. 1220 - 1227

Опубликована: Май 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

Язык: Английский

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Akkermansia muciniphila in neuropsychiatric disorders: friend or foe?

Frontiers in Cellular and Infection Microbiology, Год журнала: 2023, Номер 13

Опубликована: Июль 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.

Язык: Английский

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Glucocerebrosidase mutations and Parkinson disease

Journal of Neural Transmission, Год журнала: 2022, Номер 129(9), С. 1105 - 1117

Опубликована: Авг. 6, 2022

Abstract The discovery of glucocerebrosidase (GBA1) mutations as the greatest numerical genetic risk factor for development Parkinson disease (PD) resulted in a paradigm shift within research landscape. Efforts to elucidate mechanisms behind GBA1-associated PD have highlighted shared pathways idiopathic including loss and gain-of-function hypotheses, endoplasmic reticulum stress, lipid metabolism, neuroinflammation, mitochondrial dysfunction altered autophagy–lysosomal pathway responsible degradation aggregated misfolded a-synuclein. exhibits subtle differences phenotype progression compared counterparts notably an earlier age onset, faster motor decline greater frequency non-motor symptoms (which also constitute significant aspect prodromal phase disease). GBA1-targeted therapies been developed are being investigated clinical trials. most notable Ambroxol, small molecule chaperone, Venglustat, blood–brain-barrier-penetrant substrate reduction therapy agent. It is imperative that further studies clarify aetiology PD, enabling abundance targeted this new era precision medicine.

Язык: Английский

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

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

Опубликована: Янв. 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.

Язык: 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, Год журнала: 2023, Номер 18(1)

Опубликована: Дек. 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.

Язык: Английский

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

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(3), С. 2044 - 2044

Опубликована: Янв. 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.

Язык: Английский

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

Ageing Research Reviews, Год журнала: 2024, Номер 95, С. 102209 - 102209

Опубликована: Янв. 28, 2024

Язык: Английский

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Towards a Global View of Parkinson's Disease Genetics

Annals of Neurology, Год журнала: 2024, Номер 95(5), С. 831 - 842

Опубликована: Апрель 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.

Язык: Английский

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Synaptic dysfunction and extracellular matrix dysregulation in dopaminergic neurons from sporadic and E326K-GBA1 Parkinson’s disease patients

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

Опубликована: Фев. 19, 2024

Parkinson's disease (PD) is a neurodegenerative with both genetic and sporadic origins. In this study, we investigated the electrophysiological properties, synaptic activity, gene expression differences in dopaminergic (DA) neurons derived from induced pluripotent stem cells (iPSCs) of healthy controls, PD (sPD) patients, patients E326K-GBA1 mutations. Our results demonstrate reduced sodium currents activity DA mutations, suggesting potential contribution to pathophysiology. We also observed distinct alterations sPD neurons, which included decrease currents. RNA sequencing analysis revealed unique dysregulated pathways further supporting notion that molecular mechanisms driving may differ between patients. agreement our previous reports, Extracellular matrix Focal adhesion were among top Overall, study confirms impaired convergent functional phenotype across multiple mutations as well sPD. At transcriptome level, find brain extracellular highly involved pathology PD-associated

Язык: Английский

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