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Funded Studies

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. We believe that by understanding the genetics and the mechanistic basis of this variability, we will be able to design therapies to slow Parkinson’s progression. We have 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. We 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.

We want 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, we will find genes that influence the progression of parkinsonism, and then assess the mechanisms by which they affect disease development. We have already found that GBA and LRRK2 influence clinical rates of decline so we 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.

Next Steps for Development:
When we find genes and pathways involved in disease progression, we will develop high-throughput screens to test for compounds that modulate them. The testing of GBA and LRRK2 inhibitors in a model of pathology progression will validate this as a model in which to test drugs that may modify this development.


  • John Anthony Hardy, PhD

    London United Kingdom

  • Zane Jaunmuktane, MD, FRCPath

    London United Kingdom

  • Frances M. Platt, PhD

    Oxford United Kingdom

  • Mina Ryten, MD, PhD

    London United Kingdom

  • Maria Grazia Spillantini, PhD

    Cambridge United Kingdom

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