Research Square · Oct 27, 2026

Aerobic Exercise Ameliorates Parkinson’s Disease by Activating FGF1/ERK1/2 Signaling and Suppressing Endoplasmic Reticulum Stress

By Yang C, Wang H, LI L et al.

Objective To investigate the effects of aerobic exercise on endoplasmic reticulum stress (ERS) in mice with MPTP-induced Parkinson’s disease (PD) and to explore the potential involvement of fibroblast growth factor 1 (FGF1)/extracellular signal-regulated kinase 1/2 (ERK1/2) signaling in these effects. Methods Male C57BL/6J mice were used to establish an MPTP-induced PD model by intraperitoneal injection of MPTP. The mice were randomly assigned to the Control, PD, PD plus aerobic exercise (PDEX), FGF1 knockdown plus aerobic exercise (KDEX), and negative control plus aerobic exercise (NCEX) groups. Aerobic exercise was performed on a motorized treadmill at moderate intensity for 60 min/day, 5 days/week, for 6 weeks. We evaluated motor function using the open-field and balance beam tests. We assessed nigral neuronal injury by tyrosine hydroxylase (TH) immunohistochemistry and Nissl staining. We used Western blotting to assess α-synuclein (α-syn), FGF1, ERK1/2, and ERS-related protein expression, and transmission electron microscopy to evaluate ultrastructural changes in the endoplasmic reticulum of nigral neurons. We silenced FGF1 expression in the substantia nigra using AAV9-shFGF1 further to examine FGF1 involvement in exercise-associated ERK1/2 signaling and ERS. Results Compared with the Control group, PD mice exhibited reduced spontaneous activity, impaired motor coordination and balance, fewer TH-positive and Nissl-positive neurons in the substantia nigra, and increased α-syn expression. Ultrastructural abnormalities of the endoplasmic reticulum, characterized by dilation and disorganization, were also observed, accompanied by alterations in ERS-related markers, including p-IRE1, ATF6, ATF4, p-eIF2α, and CHOP. Compared with the PD group, aerobic exercise significantly improved motor performance, increased the number of TH-positive and Nissl-positive neurons, reduced α-syn expression, and ameliorated endoplasmic reticulum ultrastructural abnormalities. Aerobic exercise also attenuated the alterations in ERS-related markers. Further analysis showed that FGF1 expression and ERK1/2 phosphorylation were decreased in the substantia nigra of PD mice, whereas aerobic exercise significantly increased FGF1 expression and enhanced ERK1/2 phosphorylation. Compared with the NCEX group, FGF1 silencing in the KDEX group resulted in poorer motor and balance performance, fewer TH-positive and Nissl-positive neurons, and increased α-syn expression. FGF1 silencing also reduced ERK1/2 phosphorylation, as reflected by a decreased p-ERK1/2/ERK1/2 ratio, and increased ERS-related markers, including ATF6, GRP78, ATF4, p-eIF2α, and CHOP. Conclusion Aerobic exercise improves MPTP-induced motor dysfunction and nigral dopaminergic neuronal injury and attenuates abnormal ERS in PD mice. These effects are associated with increased FGF1 expression and enhanced ERK1/2 phosphorylation. FGF1 silencing attenuates exercise-associated ERK1/2 activation and is accompanied by increased ERS and reduced neuroprotection, suggesting that FGF1/ERK1/2 signaling may contribute to the regulation of ERS and nigral neuronal injury by aerobic exercise in PD. However, the direct causal relationship among FGF1, ERK1/2 signaling, and ERS remains unclear.

doi.org/10.21203/rs.3.rs-11328274/v1Open accessInterventions