TY - JOUR
T1 - Suppression of neuroinflammation and α-synuclein oligomerization by rotarod walking exercise in subacute MPTP model of Parkinson's disease
AU - Leem, Yea Hyun
AU - Park, Jin Sun
AU - Park, Jung Eun
AU - Kim, Do Youn
AU - Kim, Hee Sun
N1 - Publisher Copyright:
© 2023
PY - 2023/5
Y1 - 2023/5
N2 - Parkinson's disease (PD) belongs to an α-synucleinopathy and manifests motor dysfunction attributed to nigrostriatal dopaminergic degeneration. In clinical practice, the beneficial role of physical therapy such as motor skill learning training has been recognized in PD-linked motor defects. Nevertheless, the disease-modifying effects of motor skill learning training on PD-related pathology remain unclear. Here, we investigated the disease-modifying effects of rotarod walking exercise (RWE), a modality of motor skill learning training, in a subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. In motor function and dopaminergic degeneration, RWE improved MPTP-induced deficits. In addition, RWE enhanced the expression of neurotrophic factors BDNF/GDNF, PGC1-α, Nurr1, and p-AMPK, thereby recovering dopaminergic neuronal cell death. Moreover, RWE inhibited microglial activation and the expression of pro-inflammatory markers, such as p-IκBα, iNOS, IL-1β, TNF-α, and cathepsin D, while elevating anti-inflammatory IL-10 and TGF-β. RWE also decreased oxidative stress markers in the substantia nigra, such as 4-HNE and 8-OHdG-positive cells, while increasing Nrf2-controlled antioxidant enzymes. Regarding the effect of RWE on α-synuclein, it reduced the monomer/oligomer forms of α-synuclein and phosphorylation at serine 129. Further mechanistic studies revealed that RWE suppressed the expression of matrix metalloproteinase-3 and p-GSK3β (Y216), which play key roles in α-synuclein aggregation. These data collectively suggest that inhibition of neuroinflammation and α-synuclein oligomerization by RWE may contribute to the improvement of PD pathology.
AB - Parkinson's disease (PD) belongs to an α-synucleinopathy and manifests motor dysfunction attributed to nigrostriatal dopaminergic degeneration. In clinical practice, the beneficial role of physical therapy such as motor skill learning training has been recognized in PD-linked motor defects. Nevertheless, the disease-modifying effects of motor skill learning training on PD-related pathology remain unclear. Here, we investigated the disease-modifying effects of rotarod walking exercise (RWE), a modality of motor skill learning training, in a subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. In motor function and dopaminergic degeneration, RWE improved MPTP-induced deficits. In addition, RWE enhanced the expression of neurotrophic factors BDNF/GDNF, PGC1-α, Nurr1, and p-AMPK, thereby recovering dopaminergic neuronal cell death. Moreover, RWE inhibited microglial activation and the expression of pro-inflammatory markers, such as p-IκBα, iNOS, IL-1β, TNF-α, and cathepsin D, while elevating anti-inflammatory IL-10 and TGF-β. RWE also decreased oxidative stress markers in the substantia nigra, such as 4-HNE and 8-OHdG-positive cells, while increasing Nrf2-controlled antioxidant enzymes. Regarding the effect of RWE on α-synuclein, it reduced the monomer/oligomer forms of α-synuclein and phosphorylation at serine 129. Further mechanistic studies revealed that RWE suppressed the expression of matrix metalloproteinase-3 and p-GSK3β (Y216), which play key roles in α-synuclein aggregation. These data collectively suggest that inhibition of neuroinflammation and α-synuclein oligomerization by RWE may contribute to the improvement of PD pathology.
KW - Molecular mechanism
KW - Motor skill learning training
KW - Neuroinflammation
KW - Parkinson's disease
KW - Rotarod walking exercise
KW - α-synuclein
UR - http://www.scopus.com/inward/record.url?scp=85150393358&partnerID=8YFLogxK
U2 - 10.1016/j.neuint.2023.105519
DO - 10.1016/j.neuint.2023.105519
M3 - Article
C2 - 36931345
AN - SCOPUS:85150393358
SN - 0197-0186
VL - 165
JO - Neurochemistry International
JF - Neurochemistry International
M1 - 105519
ER -