Team Hardy

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PD Functional Genomics | 2020

Dissecting the Mechanisms Underlying Disease Progression

Study Rationale: The progression of Parkinson’s disease is very variable, with some individuals having a rapid course and others having a longer and more benign course. Team Hardy believes that by understanding the genetics and the mechanistic basis of this variability, they will be able to design therapies to slow Parkinson’s progression. Team Hardy has already found that GBA mutations lead to a rapid disease course and that LRRK2, linked to familial forms of Parkinson’s, influences the course of parkinsonism in another disease: progressive supranuclear palsy. They will test whether modulating these enzymes influences the course of pathology spread in a pre-clinical model of progression as a validation of this approach to disease treatment.

Hypothesis: Team Hardy wants to find and understand the genes that are involved in Parkinson’s progression and test whether modulating them pharmacologically influences disease progression.

Study Design: Through genetic analysis, Team Hardy will find genes that influence the progression of parkinsonism, and then assess the mechanisms by which they affect disease development. They have already found that GBA and LRRK2 influence clinical rates of decline so Team Hardy will test, in a mouse model of pathology progression, whether inhibiting these enzymes influences pathology spread and thereby develop a relevant platform to test drugs for slowing disease progression.

Impact on Diagnosis/Treatment of Parkinson’s Disease: This research will impact Parkinson’s care in three ways. First, by understanding the genetics of rate of decline, these data can be factored into clinical trial design and possibly more generally into clinical practice. Second, the identification of pathways involved in disease progression is likely to reveal further drug targets. And thirdly, the testing of GBA and LRRK2 inhibitors in a mouse model of disease progression will test this as a valid approach to treatment development.

Leadership
John Hardy, PhD
COORDINATING LEAD PI

John Hardy, PhD

University College London
Frances Platt, PhD
Co-Investigator

Frances Platt, PhD

University of Oxford
Maria Grazia Spillantini, PhD
Co-investigator

Maria Grazia Spillantini, PhD

University of Cambridge
Mina Ryten, MD, PhD
Co-Investigator

Mina Ryten, MD, PhD

University College London
Zane Jaunmuktane, MD
Co-Investigator

Zane Jaunmuktane, MD

University College London
Oke Avwenagha, PhD
Project Manager

Oke Avwenagha, PhD

University College London

Project Outcomes

Team Hardy will dissect the genetic and gene expression variability underlying differences in the rate of decline inherent in PD and move towards therapies which slow this decline. View Team Outcomes.

Team Outputs

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Overall Contributions

Here is an overview of how this team’s article findings have contributed to the PD field as of November 2023. There are two different categorizations of these contributions – one by impact to the PD community and a second by scientific theme.

Impact

Theme

Featured Output

Below is an example of a research output from the team that contributes to the ASAP mission of accelerating discoveries for PD.

The annotation and function of the Parkinson’s and Gaucher disease-linked gene GBA1 has been concealed by its protein-coding pseudogene GBAP1

GBA has previously been thought to encode a single functional protein, and mutations in GBA are important in GBA-PD and Gaucher disease. Here, Team Hardy and collaborators have evaluated the cell-specific expression of GBA and its adjacent pseudogene GBAP1 to evaluate specific isoforms. The results of this study have the potential to dramatically change our understanding of GBA-PD and reveal new paths forward relevant to understanding disease biology and potential therapeutic strategies for Gaucher and GBA-PD.

Team Accolades

Members of the team have been recognized for their contributions.

Other Team Activities

  • Working Groups: Single Cell Multi(Omics) – Mina Ryten (Co-Chair), Zane Jaunmuktane (Subgroup Lead), and Huw Morris (Subgroup Lead)
  • Interest Groups: 
    • Sequencing/Omics – Mina Ryten (Co-Chair)
    • GWAS Functional Validation – Huw Morris (Chair)

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