- 作者: Vicki Wang, Kuan-Yin Tseng, Tung-Tai Kuo, Eagle Yi-Kung Huang, Kuo-Lun Lan, Zi-Rong Chen, Kuo-Hsing Ma, Nigel H. Greig, Jin Jung, Ho-II Choi, Lars Olson, Barry J. Hoffer & Yuan-Hao Chen
- 作者服務機構: 1.Department of Neurological Surgery, Tri-Service General Hospital, Taipei, 11490, Taiwan 2.Department of Neuroscience, Karolinska Institute, 171 77, Stockholm, Sweden 3.Department of Neurosurgery, University Hospitals of Cleveland, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA 4.Department of Pathology, Tri-Service General Hospital, Taipei, 11490, Taiwan 5.Department of Pharmacology, National Defense Medical Center, Taipei, 11490, Taiwan 6.Doctoral Degree Program in Translational Medicine, National Defense Medical Center and Academia Sinica, Taipei, 11490, Taiwan 7.Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program National Institute on Aging, National Institutes of Health (NIH), Baltimore, MD, 21224, USA 8.Graduate Institute of Biology and Anatomy, National Defense Medical Center, Taipei, 11490, Taiwan 9.Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, 11490, Taiwan 10.National Defense Medical Center, Taipei, 11490, Taiwan 11.Peptron, Inc., Yuseong-gu, Daejeon, 34054, Republic of Korea
- 中文摘要:
- 英文摘要:
Background
Mitochondria are essential organelles involved in cellular energy production. Changes in mitochondrial function can lead to dysfunction and cell death in aging and age-related disorders. Recent research suggests that mitochondrial dysfunction is closely linked to neurodegenerative diseases. Glucagon-like peptide-1 receptor (GLP-1R) agonist has gained interest as a potential treatment for Parkinson's disease (PD). However, the exact mechanisms responsible for the therapeutic effects of GLP-1R-related agonists are not yet fully understood.
Methods
In this study, we explores the effects of early treatment with PT320, a sustained release formulation of the GLP-1R agonist Exenatide, on mitochondrial functions and morphology in a progressive PD mouse model, the MitoPark (MP) mouse.
Results
Our findings demonstrate that administration of a clinically translatable dose of PT320 ameliorates the reduction in tyrosine hydroxylase expression, lowers reactive oxygen species (ROS) levels, and inhibits mitochondrial cytochrome c release during nigrostriatal dopaminergic denervation in MP mice. PT320 treatment significantly preserved mitochondrial function and morphology but did not influence the reduction in mitochondria numbers during PD progression in MP mice. Genetic analysis indicated that the cytoprotective effect of PT320 is attributed to a reduction in the expression of mitochondrial fission protein 1 (Fis1) and an increase in the expression of optic atrophy type 1 (Opa1), which is known to play a role in maintaining mitochondrial homeostasis and decreasing cytochrome c release through remodeling of the cristae.
Conclusion
Our findings suggest that the early administration of PT320 shows potential as a neuroprotective treatment for PD, as it can preserve mitochondrial function. Through enhancing mitochondrial health by regulating Opa1 and Fis1, PT320 presents a new neuroprotective therapy in PD. - 中文關鍵字:
- 英文關鍵字: Glucagon-like peptide-1 receptor agonist, MitoPark mouse, Parkinson’s disease, Exenatide, Mitochondria, PT320