Parkinson’s disease (PD) is the second-most common neurodegenerative disorder, heavily characterized by the degenerative loss of dopaminergic neurons in the nigrostriatal pathway and neuroinflammation. While the prevalence of PD exhibits significant sex differences—occurring more frequently in men, though women often experience more severe advanced symptoms—the underlying molecular mechanisms driving these differences remain poorly understood. Furthermore, interleukin-6 (IL-6) has been increasingly linked to PD, yet its dual nature as both a pro-inflammatory and neuroprotective cytokine has sparked considerable controversy.

This new research, published in the Genes & Diseases journal by a collaborative scientific team from Fudan University and Tongji University, investigated the sex-dependent impact of Il6 deficiency and its downstream neuroinflammatory pathology in Parkinson's disease.

By utilizing specific Il6 knockout (KO) and wild-type (WT) mice subjected to acute MPTP intoxication or AAV-mediated α-Synuclein A53T overexpression, the researchers systematically evaluated motor behaviors and nigrostriatal degeneration. The behavioral and molecular data conclusively revealed that Il6 deficiency significantly exacerbates motor dysfunction and accelerates the depletion of dopaminergic nerve fibers. Crucially, the study uncovered a marked sex-specific vulnerability: female Il6 KO mice experienced significantly earlier and more extensive dopaminergic system injuries compared to male KO mice, accompanied by a substantially heightened reactive activation of astrocytes and microglia. Comprehensive proteomic analyses further characterized the underlying intracellular networks, revealing that this accelerated pathology in females is deeply intertwined with the dysregulation of the estrogen, MAPK, and PI3K-Akt signaling pathways.

To directly counter these severe neurodegenerative effects, the researchers explored the therapeutic potential of restoring IL-6 levels. Remarkably, in vivo evaluations confirmed that the early intraperitoneal administration of recombinant IL-6 (rIL-6) successfully reversed the aggravated pathology, partially ameliorating both motor dysfunction and striatal dopaminergic terminal depletion in the PD mice. Specifically, treating the mice with 500 ng of rIL-6 dramatically up-regulated TH protein levels and rescued TH-positive neuronal loss, fundamentally shielding the vulnerable dopaminergic neurons from neurotoxic damage.

While these comprehensive data robustly highlight the critical influence of IL-6 in regulating neuroinflammation and protecting the nigrostriatal pathway, additional clinical studies are necessary to fully isolate its central versus peripheral effects for human translation.

In conclusion, elucidating the sex-dependent neuroprotective role of IL-6 offers a powerful new strategy to combat Parkinson's disease progression. This profound finding directly positions targeted immune modulation, specifically through rIL-6 intervention, as a highly compelling therapeutic candidate for the next generation of personalized Parkinson’s disease treatments.

Reference
Title of Original Paper: Sex-dependent impact of Il6 deficiency in Parkinson’s disease mice

Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI: https://doi.org/10.1016/j.gendis.2025.101986

Funding Information:
The National Natural Science Foundation of China (No. 32271003)
The Science and Technology Commission of Shanghai Municipality, China (No. 24141901200)
The Shanghai Municipal Science and Technology Major Project (China) (No. 2018SHZDZX01), and ZJLab
The Shanghai Center for Brain Science and Brain-Inspired Technology
The Innovative Research Team of High-Level Local University in Shanghai, China

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.

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