Parkinson's disease-associated LRRK2 risk variant, G2385R, enhances Rab substrate phosphorylation and impairs neuronal integrity.
5 affiliations
- 1Department of Neurodegenerative Science, Van Andel Institute, 333 Bostwick Ave NE, Grand Rapids, MI 49503, United States.
- 2Department of Biological Sciences, University of Wisconsin-Milwaukee, 3209 N. Maryland Ave, Milwaukee, WI 53211, United States.
- 3Laboratory of Molecular Neurodegenerative Research, Brain Mind Institute, Swiss Federal Institute of Technology (EPFL), Route Cantonale, Lausanne 1015, Switzerland.
- 4Center for Neurodegeneration and Neurotherapeutics, Duke University, 3 Genome Court, Durham, NC 27710, United States.
- 5Department of Structural Biology, Van Andel Institute, 333 Bostwick Ave NE, Grand Rapids, MI 49503, United States.
Abstract
Mutations in the LRRK2 gene are the most frequent cause of familial Parkinson's disease (PD) whereas common variants are associated with an increased risk for sporadic PD. LRRK2 encodes a multi-domain protein displaying two functional enzymatic activities: GTPase and kinase. In addition to familial mutations, several common LRRK2 coding variants have been associated with PD risk in different ethnic populations. Little is known about how these coding variants modulate the risk of developing PD. In this study, we aimed to evaluate the properties of a collection of LRRK2 coding risk variants (A419V, N551K, R1398H, R1628P, M1646T, S1647T, G2385R). With the exception of G2385R, we find that coding risk variants have minimal impact on LRRK2 protein levels, GTP-binding, LRRK2 phosphorylation, and subcellular localization in human cells and primary neurons. G2385R LRRK2 exhibits reduced phosphorylation at Ser910/Ser935 and Ser1292, consistent with diminished kinase activity. Notably, however, LRRK2 variants associated with increased PD risk (R1628P, M1646T, and G2385R) significantly elevate the levels of LRRK2-mediated Rab10 phosphorylation by >two-fold in cells. In contrast, LRRK2 variants associated with reduced PD risk (N551K, R1398H, and N551K-R1398H) do not alter pRab10 levels. The G2385R LRRK2 variant significantly inhibits neurite outgrowth in primary cortical neurons compared to wild-type LRRK2. Our study indicates that LRRK2-dependent Rab phosphorylation represents a relevant readout of PD risk induced by LRRK2 variants and demonstrates that the G2385R variant creates a hyperactive kinase that can impair neuronal integrity at comparable levels to the effects of G2019S LRRK2.
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BibTeX
@article{nguyen2026parkinsons,
title = {{Parkinson's disease-associated LRRK2 risk variant, G2385R, enhances Rab substrate phosphorylation and impairs neuronal integrity.}},
author = {An Phu Tran Nguyen and Roger Moser and Nicole Bryant and Lindsey A Cunningham and Evan J Worden and Darren J Moore},
journal = {Human molecular genetics},
year = {2026},
month = sep,
doi = {10.1093/hmg/ddag103},
url = {https://europepmc.org/article/MED/42837290},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Parkinson's disease-associated LRRK2 risk variant, G2385R, enhances Rab substrate phosphorylation and impairs neuronal integrity.
AU - An Phu Tran Nguyen
AU - Roger Moser
AU - Nicole Bryant
AU - Lindsey A Cunningham
AU - Evan J Worden
AU - Darren J Moore
PY - 2026
DA - 2026/09/01
JO - Human molecular genetics
DO - 10.1093/hmg/ddag103
UR - https://europepmc.org/article/MED/42837290
AB - Mutations in the LRRK2 gene are the most frequent cause of familial Parkinson's disease (PD) whereas common variants are associated with an increased risk for sporadic PD. LRRK2 encodes a multi-domain protein displaying two functional enzymatic activities: GTPase and kinase. In addition to familial mutations, several common LRRK2 coding variants have been associated with PD risk in different ethnic populations. Little is known about how these coding variants modulate the risk of developing PD. In this study, we aimed to evaluate the properties of a collection of LRRK2 coding risk variants (A419V, N551K, R1398H, R1628P, M1646T, S1647T, G2385R). With the exception of G2385R, we find that coding risk variants have minimal impact on LRRK2 protein levels, GTP-binding, LRRK2 phosphorylation, and subcellular localization in human cells and primary neurons. G2385R LRRK2 exhibits reduced phosphorylation at Ser910/Ser935 and Ser1292, consistent with diminished kinase activity. Notably, however, LRRK2 variants associated with increased PD risk (R1628P, M1646T, and G2385R) significantly elevate the levels of LRRK2-mediated Rab10 phosphorylation by >two-fold in cells. In contrast, LRRK2 variants associated with reduced PD risk (N551K, R1398H, and N551K-R1398H) do not alter pRab10 levels. The G2385R LRRK2 variant significantly inhibits neurite outgrowth in primary cortical neurons compared to wild-type LRRK2. Our study indicates that LRRK2-dependent Rab phosphorylation represents a relevant readout of PD risk induced by LRRK2 variants and demonstrates that the G2385R variant creates a hyperactive kinase that can impair neuronal integrity at comparable levels to the effects of G2019S LRRK2.
SN - 0964-6906
SN - 1460-2083
ER -