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This study demonstrates that simvastatin, a cholesterol-lowering statin drug, reduces multiple disease-related abnormalities in dopaminergic neurons derived from Parkinson's disease patients by inhibiting RhoA, a cellular signaling protein. The researchers tested 32 different patient cell lines representing various genetic forms of Parkinson's disease and found that many, though not all, showed elevated RhoA activity compared to healthy controls. Treatment with simvastatin or direct RhoA inhibition improved neurite outgrowth, mitochondrial function, lysosomal characteristics, inflammation, and cell survival in affected neurons.
Why it matters
These findings suggest that existing statin medications could potentially be repurposed to treat certain Parkinson's disease patients, particularly those with elevated RhoA activity. The results also highlight the importance of personalized medicine approaches, as RhoA dysregulation was not universal across all genetic forms of the disease, indicating that patient stratification based on RhoA levels may be necessary for effective treatment.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
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.