LRRK2 and Parkinson’s Disease

Parkinson’s Disease (PD) is the second most prevalent neurodegenerative disease, affecting ~10 million people worldwide. One of the most commonly mutated genes in PD codes for Leucine Rich Repeat Kinase 2 (LRRK2). Autosomal dominant mutations in LRRK2 cause familial PD, while mutations in LRRK2 are risk factors for sporadic PD and increased activity of LRRK2’s kinase has been linked to the sporadic form of the disease as well. LRRK2 is a large protein with multiple domains, including both a kinase and a GTPase. A unifying theme for LRRK2 and many other PD genes is that they function in intracellular trafficking. For example, LRRK2 co-localizes with microtubules, an association that is enhanced by some PD mutations and has been shown to disrupt trafficking in model systems.

Our group is working as part of a 5-lab team supported by Aligning Science Across Parkinson’s (ASAP). Our teammates are the groups of Samara Reck-Peterson (HHMI/UCSD), Elizabeth Villa (HHMI/UCSD), Stefan Knapp (University of Frankfurt), and Florian Stengel (University of Konstanz). Together, we are combining structural biology (cryo-EM and cryo-ET), single-molecule biophysics, chemistry, biochemistry, and cell biology, to understand the role of LRRK2 in cells, and how PD-linked mutations affect its function. We are also interested in understanding the potential side effects of small-molecule therapeutics that target LRRK2 to treat PD.

Publications

* Equal contribution
# Co-corresponding authors

Reimer JM*, Dickey AM*, Lin YX*, Abrisch RG, Mathea S, Chatterjee D, Fay EJ, Knapp S, Daugherty MD, Reck-Peterson SL‡, Leschziner AE‡ (2023). Structure of LRRK1 and mechanisms of autoinhibition and activation. Nat Struct Mol Biol (Online ahead of print).

Murillo MS*, Suarez AV*, Dederer V*, Chatterjee D, Louro JA, Knapp S, Mathea S, Leschziner A (2023). Inhibition of Parkinson’s Disease-related LRRK2 by type-I and type-II kinase inhibitors: activity and structures. bioRxiv

Snead DM*, Matyszewski M*, Dickey AM*, Lin YX, Leschziner AE‡, Reck-Peterson SL‡ (2022). Structural basis for Parkinson’s Disease-linked LRRK2’s binding to microtubules. Nat Struct Mol Biol 29:1196. (Here is the bioRxiv version.)

Leschziner AE, Reck-Peterson SL (2021). Scientific Perspectives: Structural biology of LRRK2 and its interaction with microtubules. Mov Disord 36(11):2494

Deniston CK*, Salogiannis J*, Mathea S*, Snead DM, Lahiri I, Donosa O, Watanabe R, Bohning J, Shiau AK, Knapp S, Villa E, Reck-Peterson SL# and Leschziner AE# (2020). Parkinson’s Disease-related LRRK2 structure and model for microtubule interaction. Nature AAP and bioRxiv.