Abnormal Mitochondria in a Non-human Primate Model of MPTP-induced Parkinson's Disease: Drp1 and CDK5/p25 Signaling

Park, Junghyung; Seo, Ji Hun; Won, Jinyoung; Yeo, Hyeon Gu; Ahn, Yu Jin; Kim, Keon-Woo; Jin, Yeung Bae; Koo, Bon Sang; Lim, Kyung Seob; Jeong, Kang Jin; Kang, Philyong; Lee, Hwal Yong; Baek, Seung Ho; Jeon, Chang Yeop; Hong, Jung Joo; Huh, Jae Won; Kim, Young Hyun; Park, Sang Je; Kim, Sun Uk; Lee, Dong Seok; Lee, Sang Rae; Lee, Youngjeon

doi:10.5607/en.2019.28.3.414

Cited by 37 publications

(28 citation statements)

References 68 publications

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“…Recently, accumulating evidence has demonstrated that inhibition of Drp1 and/or phospho-Drp1 Ser616 ameliorates neurotoxicity and deficits in dopamine release in PD animal models. Simone et al showed that treatment with mdivi-1, a putative inhibitor of Drp1, decreased mitochondrial dysfunction and oxidative stress in α-synuclein-overexpressing rats (Bido, Soria, Fan, Bezard & Tieu, 2017;Mishra, Singh, Tiwari, Bano & Shukla, 2019;Park et al, 2019). Our findings demonstrate that MPTP-induced mitochondrial fission was significantly weaker after SA treatment through decreased protein expression of phospho-Drp1 Ser616 and is correlated with recovery of mitochondrial function.…”

Section: Discussionsupporting

confidence: 53%

Neuroprotective effect of sinapic acid on REV-ERB α modulated mitochondrial fission in Parkinson’s disease

Lee¹,

Yang²

2020

Preprint

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Background and Purpose Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide, and accumulating evidence indicates that mitochondrial dysfunction is associated with the progressive deterioration of this disease. Previous studies have shown that sinapic acid has a neuroprotective effect, but its mechanisms of action remain unclear. Experimental Approach The neuroprotective effect of sinapic acid was assayed in a PD mouse model generated by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), as well as in SH-SY5Y cells. Target protein expression was detected by western blotting and immunofluorescence. Key Results Sinapic acid treatment attenuated the behavioural defects and loss of dopaminergic neurons in the MPTP mouse model of PD. Sinapic acid also improved mitochondrial function in MPTP-treated mice, as indicated by diminished mitochondrial swelling and increased mitochondrial glutamate dehydrogenase activity. MPTP treatment increased the abundance of mitochondrial fission proteins such as dynamin-related protein 1 (Drp1) and phospho-Drp1 Ser616, while sinapic acid treatment attenuated abnormal mitochondrial fission. In addition, MPTP decreased the expression of REV-ERB α protein, whereas sinapic acid increased its expression. To elucidate the molecular mechanism linking REV-ERB α and mitochondrial fission, we used the pharmacological REV-ERB α inhibitor SR8278. Sinapic acid and SR8278 co-treatment reversed phospho-Drp1 Ser616 protein expression and the protective effect of sinapic acid in MPTP-treated mice. Conclusion and Implications Our findings demonstrated that sinapic acid protects against MPTP-induced PD by inhibiting abnormal mitochondrial fission through REV-ERB α.

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Section: Discussionsupporting

confidence: 53%

Neuroprotective effect of sinapic acid on REV-ERB α modulated mitochondrial fission in Parkinson’s disease

Lee¹,

Yang²

2020

Preprint

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“…We used three adult (12-year-old) female cynomolgus macaques ( Macaca fascicularis ), which were obtained from Suzhou Xishan Zhongke Laboratory Animal Co. (Suzhou, China) and maintained in individual indoor cages at the National Primate Research Center (NPRC) in the Korea Research Institute of Bioscience and Biotechnology (KRIBB), as described previously [ 21 , 22 ]. Animal was fed commercial monkey chow (Harlan, USA), supplemented with various fruits and water ad libitum .…”

Section: Methodsmentioning

confidence: 99%

Assessment of Hand Motor Function in a Non-human Primate Model of Ischemic Stroke

Won

Choi

et al. 2020

Exp Neurobiol

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Ischemic stroke results from arterial occlusion and can cause irreversible brain injury. A non-human primate (NHP) model of ischemic stroke was previously developed to investigate its pathophysiology and for efficacy testing of therapeutic candidates; however, fine motor impairment remains to be well-characterized. We evaluated hand motor function in a cynomolgus monkey model of ischemic stroke. Endovascular transient middle cerebral artery occlusion (MCAO) with an angiographic microcatheter induced cerebral infarction. In vivo magnetic resonance imaging mapped and measured the ischemia-induced infarct lesion. In vivo diffusion tensor imaging (DTI) of the stroke lesion to assess the neuroplastic changes and fiber tractography demonstrated three-dimensional patterns in the corticospinal tract 12 weeks after MCAO. The hand dexterity task (HDT) was used to evaluate fine motor movement of upper extremity digits. The HDT was modified for a home cage-based training system, instead of conventional chair restraint training. The lesion was localized in the middle cerebral artery territory, including the sensorimotor cortex. Maximum infarct volume was exhibited over the first week after MCAO, which progressively inhibited ischemic core expansion, manifested by enhanced functional recovery of the affected hand over 12 weeks after MCAO. The total performance time decreased with increasing success rate for both hands on the HDT. Compensatory strategies and retrieval failure improved in the chronic phase after stroke. Our findings demonstrate the recovery of fine motor skill after stroke, and outline the behavioral characteristics and features of functional disorder of NHP stroke model, providing a basis for assessing hand motor function after stroke.

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“…MPTP increased the activity of cyclin-dependent kinase 5 (CDK5) in the mouse model of PD. CDK5 was shown to be involved in the regulation of autophagy to mediate neuronal cell death and neurotoxicity [ 206 , 207 , 208 , 209 ]. Studies reported that MPTP increased LC3-II in C6 glioma cells and mouse striatum cells through CDK5 activation [ 204 ].…”

Section: Translational Applications Of Melatonin Against Nddsmentioning

confidence: 99%

Melatonin and Autophagy in Aging-Related Neurodegenerative Diseases

Luo

Sandhu

Rungratanawanich

et al. 2020

IJMS

111

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With aging, the nervous system gradually undergoes degeneration. Increased oxidative stress, endoplasmic reticulum stress, mitochondrial dysfunction, and cell death are considered to be common pathophysiological mechanisms of various neurodegenerative diseases (NDDs) such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), organophosphate-induced delayed neuropathy (OPIDN), and amyotrophic lateral sclerosis (ALS). Autophagy is a cellular basic metabolic process that degrades the aggregated or misfolded proteins and abnormal organelles in cells. The abnormal regulation of neuronal autophagy is accompanied by the accumulation and deposition of irregular proteins, leading to changes in neuron homeostasis and neurodegeneration. Autophagy exhibits both a protective mechanism and a damage pathway related to programmed cell death. Because of its “double-edged sword”, autophagy plays an important role in neurological damage and NDDs including AD, PD, HD, OPIDN, and ALS. Melatonin is a neuroendocrine hormone mainly synthesized in the pineal gland and exhibits a wide range of biological functions, such as sleep control, regulating circadian rhythm, immune enhancement, metabolism regulation, antioxidant, anti-aging, and anti-tumor effects. It can prevent cell death, reduce inflammation, block calcium channels, etc. In this review, we briefly discuss the neuroprotective role of melatonin against various NDDs via regulating autophagy, which could be a new field for future translational research and clinical studies to discover preventive or therapeutic agents for many NDDs.

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Abnormal Mitochondria in a Non-human Primate Model of MPTP-induced Parkinson's Disease: Drp1 and CDK5/p25 Signaling

Cited by 37 publications

References 68 publications

Neuroprotective effect of sinapic acid on REV-ERB α modulated mitochondrial fission in Parkinson’s disease

Neuroprotective effect of sinapic acid on REV-ERB α modulated mitochondrial fission in Parkinson’s disease

Assessment of Hand Motor Function in a Non-human Primate Model of Ischemic Stroke

Melatonin and Autophagy in Aging-Related Neurodegenerative Diseases

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