Conformation governs cellular behaviors of LRRK2 Parkinson's disease variants
- 1Weill Cornell Medicine
Abstract
Gain-of-function of leucine-rich repeat kinase 2 (LRRK2) is a common cause of Parkinson's disease (PD). In its autoinhibited state, the leucine-rich repeats of LRRK2 block the kinase active site, preventing substrate phosphorylation. Displacing the repeats ('unlatching') primes LRRK2 for activity. Preferential unlatching causes increased substrate phosphorylation of the PD allele LRRK2[R1441H], but not LRRK2[G2019S]. Here, we define a large class of PD-associated 'unlatching' mutations based on their effect on LRRK2 conformation. Unlatching mutants show increased localization to membranes, the site of LRRK2's Rab substrates. Unlatching mutants are also characterized by decreased LRRK2 S935 phosphorylation, which we define as a biomarker of conformation. This framework resolves the mechanism of variants such as I2020T, which structural studies could not predict. Overall, we establish unlatching as a unifying mechanism for most PD-linked variants and describe measurable readouts for identifying LRRK2-driven disease.
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BibTeX
@misc{hatch2026conformation,
title = {{Conformation governs cellular behaviors of LRRK2 Parkinson's disease variants}},
author = {K. S. Hatch and K. J. Surridge and W. Gai and B. Quan and G. Kumar and N. Lattal and R. Abrisch and N. Pagani and A. E. Leschziner and S. L. Reck-Peterson},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.30.763152},
url = {https://www.biorxiv.org/content/10.64898/2026.10.30.763152v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Conformation governs cellular behaviors of LRRK2 Parkinson's disease variants
AU - K. S. Hatch
AU - K. J. Surridge
AU - W. Gai
AU - B. Quan
AU - G. Kumar
AU - N. Lattal
AU - R. Abrisch
AU - N. Pagani
AU - A. E. Leschziner
AU - S. L. Reck-Peterson
PY - 2026
DA - 2026/10/30
PB - bioRxiv
DO - 10.64898/2026.10.30.763152
UR - https://www.biorxiv.org/content/10.64898/2026.10.30.763152v1
AB - Gain-of-function of leucine-rich repeat kinase 2 (LRRK2) is a common cause of Parkinson's disease (PD). In its autoinhibited state, the leucine-rich repeats of LRRK2 block the kinase active site, preventing substrate phosphorylation. Displacing the repeats ('unlatching') primes LRRK2 for activity. Preferential unlatching causes increased substrate phosphorylation of the PD allele LRRK2[R1441H], but not LRRK2[G2019S]. Here, we define a large class of PD-associated 'unlatching' mutations based on their effect on LRRK2 conformation. Unlatching mutants show increased localization to membranes, the site of LRRK2's Rab substrates. Unlatching mutants are also characterized by decreased LRRK2 S935 phosphorylation, which we define as a biomarker of conformation. This framework resolves the mechanism of variants such as I2020T, which structural studies could not predict. Overall, we establish unlatching as a unifying mechanism for most PD-linked variants and describe measurable readouts for identifying LRRK2-driven disease.
ER -