Parkinson’s Disease Pathogenic Variants: Cross-Ancestry Analysis and Microarray Data Validation DOI Creative Commons
Samantha Hong, Mathew J. Koretsky, Jens Lichtenberg

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 17, 2024

ABSTRACT Background Known pathogenic variants in Parkinson’s disease (PD) contribute to development but have yet be fully explored by arrays at scale. Objectives This study evaluated genotyping success of the NeuroBooster array (NBA) and determined frequencies across ancestries. Method We analyzed presence allele frequency 34 28,710 PD cases, 9,614 other neurodegenerative disorder 15,821 controls 11 ancestries within Global Genetics Program dataset. Of these, 25 were genotyped on NBA cluster plots used assess their quality. Results Genes previously predicted high or very confidence causing tend more are present ancestry groups. Twenty-five typed classified “good” (n=12), “medium” (n=4), “bad” (n=9) variants. Conclusion Our results confirm likelihood that established genes highlight importance ancestrally diverse research PD. also show usefulness as a reliable tool for rare

Language: Английский

Parkinson’s Disease Is Predominantly an Environmental Disease DOI Creative Commons

E. Ray Dorsey,

Bastiaan R. Bloem

Journal of Parkinson s Disease, Journal Year: 2024, Volume and Issue: 14(3), P. 451 - 465

Published: Jan. 12, 2024

Parkinson’s disease is the world’s fastest growing brain disorder, and exposure to environmental toxicants principal reason. In this paper, we consider alternative, but unsatisfactory, explanations for its rise, including improved diagnostic skills, aging populations, genetic causes. We then detail three that are likely among main causes of disease— certain pesticides, solvent trichloroethylene, air pollution. All ubiquitous, many affect mitochondrial functioning, all can access humans via various routes, inhalation ingestion. reach hopeful conclusion most thus preventable help create a world where increasingly rare.

Language: Английский

Citations

21
Uncovering the genetic basis of Parkinson's disease globally: from discoveries to the clinic DOI
Shen‐Yang Lim, Ai Huey Tan, Azlina Ahmad

et al.

The Lancet Neurology, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 1, 2024

Language: Английский

Citations

9
Single-nucleus multi-omics of Parkinson’s disease reveals a glutamatergic neuronal subtype susceptible to gene dysregulation via alteration of transcriptional networks DOI Creative Commons
E. Keats Shwab,

Daniel Gingerich,

Zhaohui Man

et al.

Acta Neuropathologica Communications, Journal Year: 2024, Volume and Issue: 12(1)

Published: July 2, 2024

Abstract The genetic architecture of Parkinson’s disease (PD) is complex and multiple brain cell subtypes are involved in the neuropathological progression disease. Here we aimed to advance our understanding PD complexity at a subtype precision level. Using parallel single-nucleus (sn)RNA-seq snATAC-seq analyses simultaneously profiled transcriptomic chromatin accessibility landscapes temporal cortex tissues from 12 compared control subjects granular single resolution. An integrative bioinformatic pipeline was developed applied for these snMulti-omics datasets. results identified subpopulation cortical glutamatergic excitatory neurons with remarkably altered gene expression PD, including differentially-expressed genes within risk loci genome-wide association studies (GWAS). This only neuronal showing significant robust overexpression SNCA . Further characterization this neuronal-subpopulation showed upregulation specific pathways related axon guidance, neurite outgrowth post-synaptic structure, downregulated presynaptic organization calcium response. Additionally, characterized roles three molecular mechanisms governing PD-associated subtype-specific dysregulation expression: (1) changes cis-regulatory element transcriptional machinery; (2) abundance master regulators, YY1, SP3, KLF16; (3) candidate regulatory variants high linkage disequilibrium PD-GWAS genomic impacting transcription factor binding affinities. To knowledge, study first most comprehensive interrogation multi-omics landscape cell-subtype Our findings provide new insights into precise subtype, causal genes, non-coding underlying paving way development cell- gene-targeted therapeutics halt as well biomarkers early preclinical diagnosis.

Language: Английский

Citations

8
Clinical and functional evidence for the pathogenicity of the LRRK2 p.Arg1067Gln variant DOI Creative Commons
Shen‐Yang Lim, Tzi Shin Toh, Jia Wei Hor

et al.

npj Parkinson s Disease, Journal Year: 2025, Volume and Issue: 11(1)

Published: Feb. 23, 2025

Language: Английский

Citations

1
Pharmacotherapy for Disease Modification in Early Parkinson’s Disease: How Early Should We Be? DOI Creative Commons
Philipp Mahlknecht, Werner Poewe

Journal of Parkinson s Disease, Journal Year: 2024, Volume and Issue: 14(s2), P. S407 - S421

Published: March 1, 2024

Slowing or halting progression continues to be a major unmet medical need in Parkinson's disease (PD). Numerous trials over the past decades have tested broad range of interventions without ultimate success. There are many potential reasons for this failure and much debate has focused on test 'disease-modifying' candidate drugs earliest stages disease. While generally accepted as rational approach, it is also associated with significant challenges around selection trial populations well outcomes durations. From health care perspective, intervening even earlier before at-risk subjects gone develop overt clinical at heart preventive medicine. Recent attempts framework biological definition PD aiming enable 'preclinical' subtype-specific diagnostic approaches. The present review addresses efforts towards disease-modification, including drug targets failure, novel that currently being explored disease-modification early established PD. new definitions may offer opportunities intervene earlier. We critically discuss planning 'disease-prevention' biologically defined prodromal

Language: Английский

Citations

4
Classification and Genotype–Phenotype Relationships of GBA1 Variants: MDSGene Systematic Review DOI Creative Commons
Malco Rossi, Susen Schaake, Tatiana Usnich

et al.

Movement Disorders, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 10, 2025

Depending on zygosity and the specific change, different variants in GBA1 gene can cause Parkinson's disease (PD, PARK-GBA1) with reduced penetrance, act as genetic risk factors for PD or parkinsonism, and/or lead to Gaucher's (GD). This MDSGene systematic literature review covers 27,963 patients carrying from 1082 publications 794 variants, including 13,342 other forms of parkinsonism. It provides a comprehensive overview demographic, clinical, findings an ethnically diverse sample originating 82 countries across five continents. The most frequent pathogenic likely were "N409S" (aka "N370S"; dominating among Jewish Whites), "L483P" "L444P"; Asians Hispanics), whereas common coding "E365K" (E326K), "T408M" (T369M) (both Whites). A novel finding is that early-onset predominantly Asian ethnicity, late-onset mainly White ethnicity. Motor cardinal features similar between motor complications non-motor symptoms more frequently reported "severe" than those "risk" "mild" variants. Cognitive decline was after surgical treatment, despite achieving beneficial function response. Most GD developing harbored variant, Ashkenazi showed positive response chronic levodopa treatment. With this review, we start fill gaps regarding genotype-phenotype correlations variant carriers, especially concerning PD. © 2025 Author(s). Movement Disorders published by Wiley Periodicals LLC behalf International Parkinson Disorder Society.

Language: Английский

Citations

0
Early-Onset Parkinson's Disease, Regional and National Burden, and Its Attributable Risk Factors in 204 Countries and Regions from 1990 to 2021: Results from the Global Burden of Disease Study 2021 DOI

Jiayue Wang,

Na Cheng,

Zhen Yao

et al.

Parkinsonism & Related Disorders, Journal Year: 2025, Volume and Issue: 134, P. 107778 - 107778

Published: March 10, 2025

Language: Английский

Citations

0
Biomarker-guided decision making in clinical drug development for neurodegenerative disorders DOI
Jeffrey L. Cummings, Charlotte E. Teunissen, Brian Fiske

et al.

Nature Reviews Drug Discovery, Journal Year: 2025, Volume and Issue: unknown

Published: April 4, 2025

Language: Английский

Citations

0
Biological frameworks for Parkinson’s disease: the heterogeneity SAAgged DOI
Annamaria Landolfi, Cristiano Sorrentino, Paolo Barone

et al.

Journal of Neurology, Journal Year: 2025, Volume and Issue: 272(4)

Published: April 1, 2025

Language: Английский

Citations

0
Advice to People with Parkinson’s in My Clinic: Probiotics and Prebiotics DOI Creative Commons
Jia Wei Hor, Tzi Shin Toh, Shen‐Yang Lim

et al.

Journal of Parkinson s Disease, Journal Year: 2024, Volume and Issue: 14(7), P. 1507 - 1518

Published: Aug. 23, 2024

There is increasing evidence that microbial-based therapies can be useful in people with Parkinson’s disease (PD). In this viewpoint, we provide a state-of-the-art review of the clinical and pre-clinical for probiotics prebiotics PD. Currently, short-term studies, including double-blind placebo-controlled randomized trials, have demonstrated safety, efficacy primarily improving constipation-related symptoms. Pre-clinical studies consistently reported improvements range biological markers outcomes, attenuation gut dysfunction neuroprotection. Bacteria from genus Lactobacillus Bifidobacterium been most frequently studied both while research into still limited involved resistant starch fructooligosaccharides. We practical suggestions clinicians on how to advise patients clinic regarding these popular treatments, important caveats aware of. Finally, areas further advancements are highlighted. It envisaged future, may benefit personalization based an enhanced understanding whole host factors host-microbiome interactions.

Language: Английский

Citations

2