Bradford Casey

Michael J. Fox Foundation

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Cornelis Blauwendraat

National Institutes of Health

Mike A. Nalls

National Institute on Aging

Andrew Singleton

Alzheimer's Association

Dan Vitale

Data Tecnica International (United States)

Mary B. Makarious

National Institutes of Health

Hirotaka Iwaki

Alzheimer's Association

Hampton L. Leonard

Institute on Aging

Kristin Levine

National Institute of Neurological Disorders and Stroke

Dena Hernández

National Institute on Aging

J. Raphael Gibbs

National Institute on Aging

Cooperative Institutions

National Institutes of Health

University College London

National Institute on Aging

23andMe (United States)

National Institute of Neurological Disorders and Stroke

National Hospital for Neurology and Neurosurgery

John Wiley & Sons (United States)

University of Exeter

Harvard University

Michael J. Fox Foundation

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Parkin Deficiency Increases Vulnerability to Inflammation-Related Nigral Degeneration

Journal of Neuroscience (2008)

Tamy C. Frank-Cannon Thi Anh Thu Tran Kelly A. Ruhn Terina N. Martinez John J. Hong

The loss of nigral dopaminergic (DA) neurons in idiopathic Parkinson's disease (PD) is believed to result from interactions between genetic susceptibility and environmental factors. Evidence that inflammatory processes modulate PD risk comes from prospective studies that suggest that higher plasma concentrations of a number of proinflammatory cytokines correlate with an increased risk of developing PD and chronic nonsteroidal anti-inflammatory drug regimens reduce the incidence of PD. Although loss-of-function mutations in the parkin gene cause early-onset familial PD, Parkin-deficient (parkin-/-) mice do not display nigrostriatal pathway degeneration, suggesting that a genetic factor is not sufficient, and an environmental trigger may be needed to cause nigral DA neuron loss. To test the hypothesis that parkin-/- mice require an inflammatory stimulus to develop nigral DA neuron loss, low-dose lipopolysaccaride (LPS) was administered intraperitoneally for prolonged periods. Quantitative real-time PCR and immunofluorescence labeling of inflammatory markers indicated that this systemic LPS treatment regimen triggered persistent neuroinflammation in wild-type and parkin-/- mice. Although inflammatory and oxidative stress responses to the inflammation regimen did not differ significantly between the two genotypes, only parkin-/- mice displayed subtle fine-motor deficits and selective loss of DA neurons in substantia nigra. Therefore, our studies suggest that loss of Parkin function increases the vulnerability of nigral DA neurons to inflammation-related degeneration. This new model of nigral DA neuron loss may enable identification of early biomarkers of degeneration and aid in preclinical screening efforts to identify compounds that can halt or delay the progressive degeneration of the nigrostriatal pathway.

Proinflammatory cytokine

Nigrostriatal pathway

Pars compacta

10.1523/jneurosci.3001-08.2008

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Citations (252)

Behavioral and Neurotransmitter Abnormalities in Mice Deficient for Parkin, DJ-1 and Superoxide Dismutase

PLoS ONE (2013)

Meghan R. Hennis K W Seamans Marian Marvin Bradford Casey Matthew S. Goldberg

Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by loss of neurons in the substantia nigra that project to the striatum and release dopamine. The cause of PD remains uncertain, however, evidence implicates mitochondrial dysfunction and oxidative stress. Although most cases of PD are sporadic, 5-10% of cases are caused by inherited mutations. Loss-of-function mutations in Parkin and DJ-1 were the first to be linked to recessively inherited Parkinsonism. Surprisingly, mice bearing similar loss-of-function mutations in Parkin and DJ-1 do not show age-dependent loss of nigral dopaminergic neurons or depletion of dopamine in the striatum. Although the normal cellular functions of Parkin and DJ-1 are not fully understood, we hypothesized that loss-of-function mutations in Parkin and DJ-1 render cells more sensitive to mitochondrial dysfunction and oxidative stress. To test this hypothesis, we crossed mice deficient for Parkin and DJ-1 with mice deficient for the mitochondrial antioxidant protein Mn-superoxide dismutase (SOD2) or the cytosolic antioxidant protein Cu-Zn-superoxide dismutase (SOD1). Aged Parkin-/-DJ-1-/- and Mn-superoxide dismutase triple deficient mice have enhanced performance on the rotorod behavior test. Cu/Zn-superoxide dismutase triple deficient mice have elevated levels of dopamine in the striatum in the absence of nigral cell loss. Our studies demonstrate that on a Parkin/DJ-1 null background, mice that are also deficient for major antioxidant proteins do not have progressive loss of dopaminergic neurons but have behavioral and striatal dopamine abnormalities.

SOD2

10.1371/journal.pone.0084894

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Citations (20)

Characterizing a complex CT-rich haplotype in intron 4 of SNCA using large-scale targeted amplicon long-read sequencing

npj Parkinson s Disease (2024)

Pilar Álvarez Jerez Kensuke Daida Francis P. Grenn Laksh Malik Abigail Miano‐Burkhardt

Abstract Parkinson’s disease (PD) is a common neurodegenerative disorder with a significant risk proportion driven by genetics. While much progress has been made, most of the heritability remains unknown. This is in-part because previous genetic studies have focused on the contribution of single nucleotide variants. More complex forms of variation, such as structural variants and tandem repeats, are already associated with several synucleinopathies. However, because more sophisticated sequencing methods are usually required to detect these regions, little is understood regarding their contribution to PD. One example is a polymorphic CT-rich region in intron 4 of the SNCA gene. This haplotype has been suggested to be associated with risk of Lewy Body (LB) pathology in Alzheimer’s Disease and SNCA gene expression, but is yet to be investigated in PD. Here, we attempt to resolve this CT-rich haplotype and investigate its role in PD. We performed targeted PacBio HiFi sequencing of the region in 1375 PD cases and 959 controls. We replicate the previously reported associations and a novel association between two PD risk SNVs (rs356182 and rs5019538) and haplotype 4, the largest haplotype. Through quantitative trait locus analyzes we identify a significant haplotype 4 association with alternative CAGE transcriptional start site usage, not leading to significant differential SNCA gene expression in post-mortem frontal cortex brain tissue. Therefore, disease association in this locus might not be biologically driven by this CT-rich repeat region. Our data demonstrates the complexity of this SNCA region and highlights that further follow up functional studies are warranted.

LRRK2

Amplicon

10.1038/s41531-024-00749-4

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Deep sequencing of sncRNAs reveals hallmarks and regulatory modules of the transcriptome during Parkinson’s disease progression

Nature Aging (2021)

Fabian Kern Tobias Fehlmann Ivo Violich Eric Alsop Elizabeth Hutchins

Small nucleolar RNA

10.1038/s43587-021-00042-6

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Citations (39)

Identification of genetic risk loci and causal insights associated with Parkinson's disease in African and African admixed populations: a genome-wide association study

The Lancet Neurology (2023)

Mie Rizig Sara Bandrés‐Ciga Mary B. Makarious Oluwadamilola O. Ojo Peter Wild Crea

Genome-wide Association Study

Linkage Disequilibrium

Genetic Association

10.1016/s1474-4422(23)00283-1

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Citations (68)

Shifting the trajectory of therapeutic development for neurological and psychiatric disorders

Science Translational Medicine (2023)

Dimitri Krainc William J. Martin Bradford Casey Frances E. Jensen Sarah A. Tishkoff

Clinical trials for central nervous system disorders often enroll patients with unrecognized heterogeneous diseases, leading to costly trials that have high failure rates. Here, we discuss the potential of emerging technologies and datasets to elucidate disease mechanisms and identify biomarkers to improve patient stratification and monitoring of disease progression in clinical trials for neuropsychiatric disorders. Greater efforts must be centered on rigorously standardizing data collection and sharing of methods, datasets, and analytical tools across sectors. To address health care disparities in clinical trials, diversity of genetic ancestries and environmental exposures of research participants and associated biological samples must be prioritized.

Data Sharing

10.1126/scitranslmed.adg4775

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Citations (3)

Quality Control Metrics for Whole Blood Transcriptome Analysis in the Parkinson’s Progression Markers Initiative (PPMI)

medRxiv (Cold Spring Harbor Laboratory) (2021)

Elizabeth Hutchins David W. Craig Ivo Violich Eric Alsop Bradford Casey

Abstract The Michael J. Fox Foundation’s Parkinson’s Progression Markers Initiative (PPMI) is an observational study to comprehensively evaluate Parkinson’s disease (PD) patients using imaging, biologic sampling, clinical and behavioural assessments to identify biomarkers of PD progression. As part of this study, we obtained 4,756 whole blood samples from 1,570 subjects at baseline, 0.5, 1, 2, and 3 years from enrollment in the study. We isolated RNA and performed whole transcriptome sequencing in this longitudinal cohort. Here, we describe and quantify technical variability associated with this dataset through the use of pooled reference samples, including plate distribution, RNA quality, and outliers. This large, uniformly processed dataset is available to researchers at https://www.ppmi-info.org .

10.1101/2021.01.05.21249278

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Citations (9)

Author Correction: Elucidating causative gene variants in hereditary Parkinson’s disease in the Global Parkinson’s Genetics Program (GP2)

npj Parkinson s Disease (2023)

Lara M. Lange Micol Avenali Melina Ellis Anastasia Illarionova Ignacio Juan Keller Sarmiento

10.1038/s41531-023-00560-7

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Citations (1)

Weekly versus Daily Blood Glucose Monitoring in Women with Gestational Diabetes

Journal of Investigative Medicine (2003)

Kristie Moss Bradford Casey Julie Lo Donald McIntire Kenneth J. Leveno

10.1177/108155890305100623

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Citations (0)

Accelerating Medicines Partnership: Parkinson's Disease. Genetic Resource

Movement Disorders (2021)

Hirotaka Iwaki Hampton L. Leonard Mary B. Makarious Matt Bookman Barry Landin

Abstract Background Whole‐genome sequencing data are available from several large studies across a variety of diseases and traits. However, massive storage and computation resources are required to use these data, and to achieve sufficient power for discoveries, harmonization of multiple cohorts is critical. Objectives The Accelerating Medicines Partnership Parkinson's Disease program has developed a research platform for Parkinson's disease (PD) that integrates the storage and analysis of whole‐genome sequencing data, RNA expression data, and clinical data, harmonized across multiple cohort studies. Methods The version 1 release contains whole‐genome sequencing data derived from 3941 participants from 4 cohorts. Samples underwent joint genotyping by the TOPMed Freeze 9 Variant Calling Pipeline. We performed descriptive analyses of these whole‐genome sequencing data using the Accelerating Medicines Partnership Parkinson's Disease platform. Results The clinical diagnosis of participants in version 1 release includes 2005 idiopathic PD patients, 963 healthy controls, 64 prodromal subjects, 62 clinically diagnosed PD subjects without evidence of dopamine deficit, and 705 participants of genetically enriched cohorts carrying PD risk‐associated GBA variants or LRRK2 variants, of whom 304 were affected. We did not observe significant enrichment of pathogenic variants in the idiopathic PD group, but the polygenic risk score was higher in PD both in nongenetically enriched cohorts and genetically enriched cohorts. The population analysis showed a correlation between genetically enriched cohorts and Ashkenazi Jewish ancestry. Conclusions We describe the genetic component of the Accelerating Medicines Partnership Parkinson's Disease platform, a solution to democratize data access and analysis for the PD research community. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article is a U.S. Government work and is in the public domain in the USA.

LRRK2

Genome-wide Association Study

10.1002/mds.28549

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Citations (90)