image: (A–D) TH protein levels in the striatum of female mice (A, B) and male mice (C, D) at 3 days post-MPTP administration. β-actin served as the loading control. n = 3–5. (E–H) Density of TH-positive nerve fibers in the striatum of female mice (E, G) at 3 days post-MPTP administration (n = 4 or 5) and male mice (F, H) at 7 days post-MPTP administration (n = 5). Scale bar: 200 μm and 50 μm (zoom). (I–L) Counting of TH-positive cells in the SNpc of female mice (I, K) at 3 days post-MPTP administration (n = 4 or 5) and male mice (J, L) at 1 day, 3 days, and 7 days post-MPTP administration (n = 4 or 5). Scale bar: 200 μm. ∗P < 0.05, ∗∗P < 0.01, and ∗∗∗∗P < 0.0001.
Credit: Fangzheng Chen, Yufei Duan, Mengze Wang, Zhaolin Liu, Jiayin Zhao, Guangchun Fan, Yongtao He, Hongtian Dong, Xiaoshuang Zhang, Rong Fang, Yunhe Zhang, Xin Yan, Chenye Shen, Xiwen Tang, Yuanyuan Ma, Mei Yu, Renyuan Zhou, Jian Fei, Fang Huang.
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
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