Parkinson’s disease (PD) is a devastating neurodegenerative condition that affects up to 10 million people worldwide and there is no cure. The overarching aim of the Sammler Group is to define biological markers and elucidate the underlying mechanisms of PD using predominantly human biological samples.

We are particularly interested in the role of the lysosome and other organelles and the role of the Leucine rich repeat kinase 2 (LRRK2) (1). Our goal is to identify and validate markers for diagnosing PD / PD subtypes, measuring PD risk, progression and prognosis as well as stratifying patients for novel disease modifying treatments. We take translational multidisciplinary approaches, collaborate with leading national and international clinical experts and scientists, emphasise meaningful patient and public engagement and support the development of early career scientists.

Project description

This project will be embedded in the newly funded ‘The Michael J Fox Foundation LRRK2 Therapeutic Exchange Initiative’ (MJFF-LITE) and in close collaboration and co-supervision by Professor Dario Alessi (second PhD supervisor). Clinically, PD is highly heterogenous but there is a ‘LRRK2 driven’ subtype that needs to be better defined as these patients will most likely benefit from LRRK2 targeting treatment strategies. Pathogenic variants (mutations) in LRRK2 hyperactive the LRRK2 kinase with subsequent RabGTPase hyperactivation leading to dysregulated endolysosomal trafficking and lysosomal dysfunction (1). Additionally, LRRK2 kinase hyperactivation occurs in a large number of novel LRRK2 variant carriers (‘Variants of unknown clinical significance’ or VUS) (2,3), PD due to mutations in other monogenic PD syndromes (e.g. VPS35, Rab32) (4,5) and likely in a subgroup of PD patients where the underlying cause is not known (idiopathic PD). Additionally, the LRRK2 and GBA1 signalling pathways interact with each other and heterozygous variants in GBA1 represent a significant risk factor for PD. We have previously leveraged Rab phosphorylation as a readout for LRRK2 kinase activity in peripheral blood neutrophils and monocytes and urine BMPs as a proxy for LRRK2 associated endolysosomal dysfunction (4,6-8). For this project we will profile a large number of genetic and idiopathic PD patients and matched controls by leveraging novel organelleIP technology (e.g. lysosomes, mitochondria, Golgi) for stratifying and quantifying LRRK2-driven PD (9).

This project will provide training expertise in the state-of-the-art translational research, biochemistry, molecular biology, cell signalling, mass spectrometry, data analysis, scientific collaboration, patient and public involvement as well as statistics, communication, written and oral presentation and working in a team. This project also offers opportunities to collaborate with other international clinical sites and to travel there to be involved in aspects of the collection of biological samples. For any informal queries, please contact Dr. Esther Sammler: [email protected]

At the MRC PPU, as well as the possibility of a PhD in one particular lab, we offer the possibility of two 4.5-month rotations in labs of their choice. A range of other projects from MRC PPU scientists are advertised here . Rotations provide valuable experience and help with deciding on the choice of PhD project and research group.

To apply for this project, or any of our other PhD projects, please complete the following application

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When completing the application, there will be space to copy over your CV, contact details of three referees and a cover letter explaining why you have chosen to apply to MRC PPU.

The closing date for applications is 31st October 2024. Applications from overseas students are welcome.

If you have any questions or need to get in touch with us, please email us at [email protected] .