Esther Sammler | Honorary Clinical PI

Pubmed | Biography


Parkinson’s disease

Parkinson’s disease (PD) is a common neurodegenerative condition. Although the underlying cause remains unknown, intensive research has led to the discovery of ~20 genes that when mutated cause genetic forms of Parkinsonism. The MRC PPU has a track record of elucidating critical signal transduction pathways in Parkinson’s disease (PD), mainly related to protein kinases and E3-ubiquitin-ligases associated with PD. The expectation is that the translation of such knowledge will be relevant to idiopathic PD.

As a clinician scientist, I am interested in accelerating the application of scientific discoveries via target validation to facilitate the development of biomarkers and novel treatments. To achieve this, I collaborate with other researchers, clinicians, and people affected by PD – my patients. I am also one of directors of the newly established Dundee Edinburgh Parkinson’s Initiative. I am uniquely positioned to bridge the divide between the clinical environment and the research laboratory and ensure that research advances have an immediate translational impact.

My recent focus on the LRRK2 kinase exemplifies the approach I am taking:LRRK2 is the most frequently mutated gene in PD. All pathogenic mutations result in hyperactivation of the LRRK2 kinase and this is thought to be causal to the development of LRRK2-associated PD. The LRRK2 kinase offers the prospect for disease-modifying treatments. We have recently established an assay to interrogate the LRRK2 kinase pathway by measuring the phosphorylation of one of its targets, Rab10, in human peripheral blood neutrophils. This is a major step forward in providing insight into the physiological activity of the LRRK2 kinase pathway in humans. It will allow the identification of individuals with increased levels of LRRK2 controlled Rab10 phosphorylation and potentially aid in pharmacokinetic and target engagement studies in future LRRK2 inhibitor trials. 

The incomplete penetrance of LRRK2 mutations – the majority of carriers may never develop PD - highlights the importance of other factors such as lifestyle, environment, gut microbiome, and infection in developing LRRK2-associated PD. LRRK2 is highly expressed in immune cells and growing evidence points towards a role of LRRK2 in host defense mechanism as well as the speculation that mutational LRRK2 kinase activation may protect against infection in earlier life, but increase susceptible for developing PD in later life. Inflammation as demonstrated by microglia activation is also one of the histopathological hallmarks in idiopathic PD. I am therefore curious in finding out more about the role of LRRK2 in human defense mechanisms and how LRRK2 inhibition might result in perturbation thereof.

Overall, I am interested in aligning mechanistic insight into disease pathways with genetics and clinical phenotyping of people affected by PD with the aims of 1) defining the role of LRRK2 signaling in idiopathic PD, 2) studying the crosstalk between LRRK2 and other monogentic PD syndromes and 3) offer stratified medicines for disease modification and prevention to my patients in the future.

Selected Publications

Fan, Y., Howden, A., Sarhan, A.R., Lis, P., Ito, G., Martinez, T.N., Brockmann, K., Gasser, T., Alessi D.R. & Sammler, E. (2018) Interrogating Parkinson’s disease LRRK2 kinase pathway activity by assessing Rab10 phosphorylation in human neutrophils Biochemical Journal 475 23.44
Alessi D.R. & Sammler, E. (2018) LRRK2 in Parkinson’s Disease Science 360(6384) 36-37