间歇性禁食可减轻帕金森病小鼠模型中的α-突触核蛋白病理变化和功能衰退。

Intermittent fasting reduces alpha-synuclein pathology and functional decline in a mouse model of Parkinson's disease.

作者信息

Szegő Éva M, Höfs Lennart, Antoniou Anna, Dinter Elisabeth, Bernhardt Nadine, Schneider Anja, Di Monte Donato A, Falkenburger Björn H

机构信息

Department of Neurology, TU Dresden, Dresden, Germany.

German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.

出版信息

Nat Commun. 2025 May 14;16(1):4470. doi: 10.1038/s41467-025-59249-5.

DOI:10.1038/s41467-025-59249-5

PMID:40368903

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12078643/

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder characterized by dopaminergic neuron degeneration and α-synuclein (aSyn) accumulation. Environmental factors play a significant role in PD progression, highlighting the potential of non-pharmacological interventions. This study investigates the therapeutic effects of intermittent fasting (IF) in an rAAV-aSyn mouse model of PD. IF, initiated four weeks post-induction of aSyn pathology, improved motor function and reduced dopaminergic neuron and axon terminal degeneration. Additionally, IF preserved dopamine levels and synaptic integrity in the striatum. Mechanistically, IF enhanced autophagic activity, promoting phosphorylated-aSyn clearance and reducing its accumulation in insoluble brain fractions. Transcriptome analysis revealed IF-induced modulation of inflammation-related genes and microglial activation. Validation in primary cultures confirmed that autophagy activation and inflammatory modulators (CCL17, IL-36RN) mitigate aSyn pathology. These findings suggest that IF exerts neuroprotective effects, supporting further exploration of IF and IF-mimicking therapies as potential PD treatments.

摘要

帕金森病（PD）是一种神经退行性疾病，其特征为多巴胺能神经元变性和α-突触核蛋白（aSyn）积累。环境因素在PD进展中起重要作用，这凸显了非药物干预的潜力。本研究调查了间歇性禁食（IF）在PD的重组腺相关病毒-aSyn小鼠模型中的治疗效果。在aSyn病理学诱导四周后开始的IF改善了运动功能，并减少了多巴胺能神经元和轴突终末的变性。此外，IF维持了纹状体中的多巴胺水平和突触完整性。从机制上讲，IF增强了自噬活性，促进了磷酸化aSyn的清除，并减少了其在不溶性脑组分中的积累。转录组分析揭示了IF诱导的炎症相关基因的调节和小胶质细胞活化。原代培养中的验证证实，自噬激活和炎症调节剂（CCL17、IL-36RN）减轻了aSyn病理学。这些发现表明IF具有神经保护作用，支持进一步探索IF和模拟IF的疗法作为潜在的PD治疗方法。