We are studying the consequences of activating mutations in the Leucine Rich Repeat Kinase 2 that underlie inherited Parkinson's disease, the second most common neurodegenerative disorder. LRRK2 kinase phosphorylates Rab GTPases and we are studying how thie phosphorylation triggers cell biological changes in neurons and astrocytes. We discovered that Rab GTPase phosphorylation blocks primary cilia formation in cell culture and in specific brain regions. Our approaches range from single molecule analysis of the membrane recruitment and activation of the kinase to understanding how loss of cilia in the dorsal striatum blocks Hedgehog signal sensing, leading to loss of dopaminergic neurons in the Substantia nigra and cholinergic neurons in the striatum. We are seeking candidates with a background in biochemistry, cell biology or neurobiology to join our multidisciplinary efforts to understand the role of pathogenic LRRK2 kinase in Parkinson's disease at a molecular level.
Pathogenic LRRK2 control of primary cilia and Hedgehog signaling in neurons and astrocytes of mouse brain.
Shahzad S Khan, Yuriko Sobu, Herschel S Dhekne, Francesca Tonelli, Kerryn Berndsen, Dario R Alessi, Suzanne R Pfeffer
eLife. 2021; 10: e67900. PMCID: PMC8550758
Pathogenic LRRK2 regulates ciliation probability upstream of tau tubulin kinase 2 via Rab10 and RILPL1 proteins
Yuriko Sobu, Paulina S. Wawro, Herschel S. Dhekne, Wondwossen M. Yeshaw, Suzanne R. Pfeffer
Proc Natl Acad Sci U S A. 2021 Mar 9; 118(10): e2005894118. PMCID: PMC7958464
PPM1H phosphatase counteracts LRRK2 signaling by selectively dephosphorylating Rab proteins
Kerryn Berndsen, Pawel Lis, Wondwossen M Yeshaw, Paulina S Wawro, Raja S Nirujogi, Melanie Wightman, Thomas Macartney, Mark Dorward, Axel Knebel, Francesca Tonelli, Suzanne R Pfeffer, Dario R Alessi eLife. 2019; 8: e50416. Published online 2019 Oct 30. doi: 10.7554/eLife.50416 PMCID: PMC6850886