Koşu bandı egzersizi miR-7/Drp1/PINK1 ekseni ile mitokondriyal ve sinaptik fonksiyonları düzenleyerek PD farelerde motor işlevini geliştirir.

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Abstract Background Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the degeneration of dopaminergic neurons in the substantia nigra. Exercise can delay PD progression and improve motor symptoms. However, the underlying molecular mechanisms remain unclear. Whether exercise exerts protective effects by reshaping microRNA (miRNA) expression profiles remains unclear. This study aims to explore differential miRNA expression and their targeted pathways mediated by moderate-intensity exercise, and to reveal novel mechanisms of neuroprotection in PD. Methods Eight-week-old male C57BL/6 mice were randomly divided into normal control (NC), PD model (PD), and PD exercise (PE) groups. The PE group received 8 weeks of treadmill exercise. SH‑SY5Y cells were treated with MPP⁺ to establish a cellular PD model. Motor functions were assessed using pole, hanging, and gait tests. Immunohistochemical staining detected the levels of the rate-limiting enzyme of catecholamine biosynthesis Tyrosine hydroxylase (TH) and the pathological marker of PD α-synuclein (α-syn). Immunofluorescence staining detected TH, α‑syn, and the neurogenesis markers BrdU and NeuN. Synaptic currents in the substantia nigra were recorded by brain slice patch‑clamp. Cell viability was measured by CCK‑8 assay, and mitochondrial membrane potential was assessed by JC‑1 staining. RNA sequencing was performed to screen for differentially expressed miRNAs. ATP content was determined by biochemical assay. Dual‑luciferase assay verified the interaction between miR‑7 and its target genes. Western blot detected the expression of TH, α-syn, the synaptic proteins synaptophysin (SYN) and postsynaptic density 95 (PSD95), the mitochondrial fission proteins dynamin-related protein1 (Drp1), phosphorylated Drp1 (p-Drp1), and mitochondria fission protein1 (FIS1), the mitophagy-related proteins PTEN induced putative kinase 1 (PINK1), Parkin, microtubule-associated proteins 1A/1B light chain 3A/B (LC3A/B), ubiquitin‑binding protein p62 (p62). qRT‑PCR detected the expression of miR‑7, Drp1, PINK1, and Parkin. Results PD group showed improved motor coordination and gait function after 8 weeks of treadmill exercise. Neurodegeneration was alleviated, and synaptic plasticity and mitochondrial function were enhanced in PD group. In PD mice and MPP⁺‑treated SH‑SY5Y cells, miR‑7 expression was significantly decreased. 8 weeks of treadmill exercise increased miR‑7 expression in PD mice. Exercise regulated the Drp1/PINK1 pathway via miR‑7. Overexpression of miR‑7 inhibited MPP⁺‑induced excessive mitochondrial fission, and alleviated mitochondrial dynamics imbalance and mitochondrial dysfunction, and improved synaptic function. Conclusion 8 weeks of treadmill exercise regulates mitochondrial and synaptic functions via the miR-7/Drp1/PINK1 pathway, thereby improving motor function and delaying PD progression in PD mice.

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