Simvastatin attenuates disease phenotypes in human induced pluripotent stem cell models of familial Parkinson's disease through RhoA inhibition
- 1University of Southern Denmark
Abstract
Background: Statins have gained increasing interest for their potential therapeutic effect in Parkinson's disease (PD). Beyond their cholesterol-lowering effect, statins decrease synthesis of isoprenoids, which is believed to account for their pleiotropic effects. Isoprenylation is important for proper membrane localization and function of the Rho GTPases, including RhoA. RhoA signalling has emerged as a possible underlying signalling pathway involved in the pathogenesis of PD and other neurodegenerative diseases. Methods: In the present study, we investigated the effects of simvastatin on neurodegeneration-associated phenotypes using human induced pluripotent stem cell-derived dopaminergic (DA) neurons from both PD patients and isogenic PARK2-/- cell lines. The dependence on RhoA was confirmed using direct RhoA inhibition using rhosin. Assessed phenotypes included structural integrity, mitochondrial and lysosomal characteristics, cytokine secretion, and cell viability. To understand the relevance of RhoA in PD, RhoA activity was measured in 32 PD patient iPSC-derived lines with different familial PD-related mutations and in healthy controls. Results: Simvastatin rescued multiple PD-associated phenotypes, including impaired DA neurite outgrowth, mitochondrial and lysosomal alterations, cytokine release, and cell death. RhoA inhibition was associated with changes in mitophagy- and autophagy-related markers, suggesting improved autophagic and mitophagic turnover. Furthermore, we performed the first systematic screen of RhoA activity across 32 iPSC-derived DA neuron lines representing multiple genetic forms of PD (PINK1 loss of function, parkin loss of function, LRRK2 (G2019S), LRRK2 (R1441C), GBA (L44P), GBA (N370S), A53T, and SNCA triplication) and healthy controls. RhoA activity was perturbated across several genetic forms of PD subtypes and was significantly increased in many, although not all, patient lines compared with healthy controls, highlighting disease heterogeneity and supporting RhoA dysregulation as a shared pathogenic mechanism in a subset of PD. Conclusions: Our findings identify aberrant RhoA signalling as a convergent pathogenic mechanism across multiple forms of genetic PD and demonstrate that simvastatin ameliorates PD-associated phenotypes through RhoA inhibition. These results support RhoA as a promising therapeutic target while emphasizing the importance of patient stratification based on RhoA activity.
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BibTeX
@misc{schmidt2026simvastatin,
title = {{Simvastatin attenuates disease phenotypes in human induced pluripotent stem cell models of familial Parkinson's disease through RhoA inhibition}},
author = {S. I. Schmidt and J. Okarmus and M. Ryding and I. K. Skousen and N. F. Broner Jensen and E. B. Christensen and L. S. Winkelmann and A. D. Juhl and M. Klaebel and M. Blaabjerg and K. Freude and D. Wustner and R. Wade-Martins and B. Ryan and M. Meyer},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.26.747232},
url = {https://www.biorxiv.org/content/10.64898/2026.08.26.747232v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Simvastatin attenuates disease phenotypes in human induced pluripotent stem cell models of familial Parkinson's disease through RhoA inhibition
AU - S. I. Schmidt
AU - J. Okarmus
AU - M. Ryding
AU - I. K. Skousen
AU - N. F. Broner Jensen
AU - E. B. Christensen
AU - L. S. Winkelmann
AU - A. D. Juhl
AU - M. Klaebel
AU - M. Blaabjerg
AU - K. Freude
AU - D. Wustner
AU - R. Wade-Martins
AU - B. Ryan
AU - M. Meyer
PY - 2026
DA - 2026/08/26
PB - bioRxiv
DO - 10.64898/2026.08.26.747232
UR - https://www.biorxiv.org/content/10.64898/2026.08.26.747232v1
AB - Background: Statins have gained increasing interest for their potential therapeutic effect in Parkinson's disease (PD). Beyond their cholesterol-lowering effect, statins decrease synthesis of isoprenoids, which is believed to account for their pleiotropic effects. Isoprenylation is important for proper membrane localization and function of the Rho GTPases, including RhoA. RhoA signalling has emerged as a possible underlying signalling pathway involved in the pathogenesis of PD and other neurodegenerative diseases. Methods: In the present study, we investigated the effects of simvastatin on neurodegeneration-associated phenotypes using human induced pluripotent stem cell-derived dopaminergic (DA) neurons from both PD patients and isogenic PARK2-/- cell lines. The dependence on RhoA was confirmed using direct RhoA inhibition using rhosin. Assessed phenotypes included structural integrity, mitochondrial and lysosomal characteristics, cytokine secretion, and cell viability. To understand the relevance of RhoA in PD, RhoA activity was measured in 32 PD patient iPSC-derived lines with different familial PD-related mutations and in healthy controls. Results: Simvastatin rescued multiple PD-associated phenotypes, including impaired DA neurite outgrowth, mitochondrial and lysosomal alterations, cytokine release, and cell death. RhoA inhibition was associated with changes in mitophagy- and autophagy-related markers, suggesting improved autophagic and mitophagic turnover. Furthermore, we performed the first systematic screen of RhoA activity across 32 iPSC-derived DA neuron lines representing multiple genetic forms of PD (PINK1 loss of function, parkin loss of function, LRRK2 (G2019S), LRRK2 (R1441C), GBA (L44P), GBA (N370S), A53T, and SNCA triplication) and healthy controls. RhoA activity was perturbated across several genetic forms of PD subtypes and was significantly increased in many, although not all, patient lines compared with healthy controls, highlighting disease heterogeneity and supporting RhoA dysregulation as a shared pathogenic mechanism in a subset of PD. Conclusions: Our findings identify aberrant RhoA signalling as a convergent pathogenic mechanism across multiple forms of genetic PD and demonstrate that simvastatin ameliorates PD-associated phenotypes through RhoA inhibition. These results support RhoA as a promising therapeutic target while emphasizing the importance of patient stratification based on RhoA activity.
ER -