Atorvastatin Shows Limited Disease-Modifying Effects in an A53T α-Synuclein Mouse Model of Parkinson's Disease.

Overview

1. Department of Geriatrics, Maoming People’s Hospital, Maoming, Guangdong China
2. Guangzhou Medical University, Guangzhou, Guangdong China
3. Department of Oncology I, Maoming People’s Hospital, Maoming, Guangdong China
4. Department of Emergency, Guangdong Provincial Farm Reclamation Central Hospital, Zhanjiang, Guangdong China
5. Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong China

Abstract

Neuroprotective effects of statins in Parkinson’s disease (PD) remain uncertain, and their activity in genetic α-synuclein (αSyn) disease models has been insufficiently characterized. We evaluated atorvastatin (ATO) in a mouse model with nigral overexpression of human A53T-mutant αSyn. Mice received ATO by oral gavage at 10 mg/kg/day for 5 weeks and were assessed using behavioral testing, neuropathological assessment, brain transcriptomics, and molecular docking. ATO inhibited cholesterol biosynthesis-related transcriptional programs and broadly remodeled lipid metabolism-associated networks, but did not lead to functional or histopathological benefit. ATO did not ameliorate motor deficits, restore dopaminergic markers, or reduce αSyn protein levels or pSer129-αSyn immunoreactivity. Transcriptomic analysis further showed that ATO failed to reverse the core disease-associated signature induced by A53T αSyn overexpression and instead increased SNCA mRNA. Targeted RNA-seq and western blot analyses showed no parallel increase in Prkn, Gba1, or Lamp2 transcript abundance or in PARKIN, GBA1, or LAMP2A protein expression. Molecular docking, used here as an exploratory structural comparison, suggested a relatively weak predicted interaction between ATO and αSyn when compared with several other statins and provided supportive context for the lack of efficacy. Overall, our findings indicate limited efficacy of ATO in this αSyn-driven setting and support further comparative evaluation of individual statins across complementary PD models.

Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s12640-026-00825-y.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

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• uniprot.org/uniprotkb, at UniProt; found in the text, “Molecular Docking”

Data Availability

All data collections employed and analyzed for the purposes of this research are available from the corresponding author on request from qualified investigators.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 3, 28 September 2026

• Publisher: n/a → Springer Science+Business Media

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 7 authors, 5 keywords, 12 MeSH terms, 2 funders, 37 references.

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This paper

Wei, L., Hua, J., Tang, S., Lei, J., Li, G., Wei, L., & Mo, M. (2026). Atorvastatin Shows Limited Disease-Modifying Effects in an A53T α-Synuclein Mouse Model of Parkinson's Disease. Neurotoxicity research, 44(5), 51. https://doi.org/10.1007/s12640-026-00825-y

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