Chemical Genetic Targeting of the LRRK2 GTPase Domain
- 1Department of Cellular and Molecular Pharmacology and Howard Hughes Medical Institute, University of California San Francisco, San Francisco, CA 94158, USA
Abstract
Genetic variants throughout the multi-domain protein leucine-rich repeat kinase 2 (LRRK2) gene are the most common cause of autosomal dominant Parkinson's disease, and the most prevalent Parkinson's-associated LRRK2 variants enhance kinase activity. Hence, the kinase domain has been extensively targeted for therapeutic development. However, clinical progression of LRRK2 kinase inhibitors has been limited by on-target peripheral toxicities linked to strong kinase suppression, raising the question of whether targeting LRRK2 kinase activity through other means could offer a more tunable therapeutic window. LRRK2 is one of two proteins in the human proteome that possess a Roc-COR GTPase domain in tandem with a kinase domain, and the GTPase domain has been shown to intramolecularly regulate kinase output. Here, we ask whether the Roc-COR GTPase can be targeted as an alternative approach to downregulate kinase activity. We utilize a chemical genetic approach to sensitize LRRK2 to existing GTPase inhibitors and show that pharmacologically engaging the Roc-COR GTPase domain in cells decreases but does not fully inhibit LRRK2-mediated Rab10 T73 phosphorylation. This study lays the groundwork for future efforts directed at the development of pharmacological inhibitors for the LRRK2 GTPase, providing an alternative approach for therapies targeting LRRK2-driven Parkinson's disease.
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BibTeX
@misc{prorok2026chemical,
title = {{Chemical Genetic Targeting of the LRRK2 GTPase Domain}},
author = {R. E. Prorok and L. Y. Zhu and V. Bowcut and H. Wu and K. Z. Guiley and J. Morstein and K. Shokat},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.03.749217},
url = {https://www.biorxiv.org/content/10.64898/2026.09.03.749217v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Chemical Genetic Targeting of the LRRK2 GTPase Domain
AU - R. E. Prorok
AU - L. Y. Zhu
AU - V. Bowcut
AU - H. Wu
AU - K. Z. Guiley
AU - J. Morstein
AU - K. Shokat
PY - 2026
DA - 2026/09/03
PB - bioRxiv
DO - 10.64898/2026.09.03.749217
UR - https://www.biorxiv.org/content/10.64898/2026.09.03.749217v1
AB - Genetic variants throughout the multi-domain protein leucine-rich repeat kinase 2 (LRRK2) gene are the most common cause of autosomal dominant Parkinson's disease, and the most prevalent Parkinson's-associated LRRK2 variants enhance kinase activity. Hence, the kinase domain has been extensively targeted for therapeutic development. However, clinical progression of LRRK2 kinase inhibitors has been limited by on-target peripheral toxicities linked to strong kinase suppression, raising the question of whether targeting LRRK2 kinase activity through other means could offer a more tunable therapeutic window. LRRK2 is one of two proteins in the human proteome that possess a Roc-COR GTPase domain in tandem with a kinase domain, and the GTPase domain has been shown to intramolecularly regulate kinase output. Here, we ask whether the Roc-COR GTPase can be targeted as an alternative approach to downregulate kinase activity. We utilize a chemical genetic approach to sensitize LRRK2 to existing GTPase inhibitors and show that pharmacologically engaging the Roc-COR GTPase domain in cells decreases but does not fully inhibit LRRK2-mediated Rab10 T73 phosphorylation. This study lays the groundwork for future efforts directed at the development of pharmacological inhibitors for the LRRK2 GTPase, providing an alternative approach for therapies targeting LRRK2-driven Parkinson's disease.
ER -