1.Prophylactic effects of swimming exercise on autophagy-induced muscle atrophy in diabetic rats.
Youngjeon LEE ; Joo Heon KIM ; Yunkyung HONG ; Sang Rae LEE ; Kyu Tae CHANG ; Yonggeun HONG
Laboratory Animal Research 2012;28(3):171-179
Diabetes decreases skeletal muscle mass and induces atrophy. However, the mechanisms by which hyperglycemia and insulin deficiency modify muscle mass are not well defined. In this study, we evaluated the effects of swimming exercise on muscle mass and intracellular protein degradation in diabetic rats, and proposed that autophagy inhibition induced by swimming exercise serves as a hypercatabolic mechanism in the skeletal muscles of diabetic rats, supporting a notion that swimming exercise could efficiently reverse the reduced skeletal muscle mass caused by diabetes. Adult male Sprague-Dawley rats were injected intraperitoneally with streptozotocin (60 mg/kg body weight) to induce diabetes and then submitted to 1 hr per day of forced swimming exercise, 5 days per week for 4 weeks. We conducted an intraperitoneal glucose tolerance test on the animals and measured body weight, skeletal muscle mass, and protein degradation and examined the level of autophagy in the isolated extensor digitorum longus, plantaris, and soleus muscles. Body weight and muscle tissue mass were higher in the exercising diabetic rats than in control diabetic rats that remained sedentary. Compared to control rats, exercising diabetic rats had lower blood glucose levels, increased intracellular contractile protein expression, and decreased autophagic protein expression. We conclude that swimming exercise improves muscle mass in diabetes-induced skeletal muscle atrophy, suggesting the activation of autophagy in diabetes contributes to muscle atrophy through hypercatabolic metabolism and that aerobic exercise, by suppressing autophagy, may modify or reverse skeletal muscle wasting in diabetic patients.
Adult
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Animals
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Atrophy
;
Autophagy
;
Blood Glucose
;
Body Weight
;
Exercise
;
Glucose Tolerance Test
;
Humans
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Hyperglycemia
;
Insulin
;
Male
;
Muscle, Skeletal
;
Muscles
;
Muscular Atrophy
;
Proteolysis
;
Rats
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Rats, Sprague-Dawley
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Streptozocin
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Swimming
2.Autophagy contributes to retardation of cardiac growth in diabetic rats.
Youngjeon LEE ; Yunkyung HONG ; Sang Rae LEE ; Kyu Tae CHANG ; Yonggeun HONG
Laboratory Animal Research 2012;28(2):99-107
Diabetes mellitus is a major predictor of heart failure, although the mechanisms by which the disease causes cardiomyopathy are not well understood. The purpose of this study was to determine whether prolonged exposure of cardiomyocytes to high glucose concentrations induces autophagy and contributes to cardiomyopathy. Interestingly, there were no differences in the autophagic activation produced by different glucose concentrations. However, cell viability was decreased by high glucose. In the diabetic rats, we found a higher level of microtubule-associated protein light chain 3 (LC3) expression and a reduction in the size of the left ventricle (LV) (P<0.05) caused by growth retardation, suggesting activated autophagy. Our in vitro findings indicate that hyperglycemic oxidative stress induces autophagy, and our in vivo studies reveal that autophagy is involved in the progression of pathophysiological remodeling of the heart. Taken together, the studies suggest that autophagy may play a role in the pathogenesis of juvenile diabetic cardiomyopathy.
Animals
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Autophagy
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Cardiomyopathies
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Cell Survival
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Diabetes Mellitus
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Diabetic Cardiomyopathies
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Glucose
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Heart
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Heart Failure
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Heart Ventricles
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Hyperglycemia
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Light
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Myocytes, Cardiac
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Oxidative Stress
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Rats
3.Differential expression of caveolins and myosin heavy chains in response to forced exercise in rats.
Sookyoung PARK ; Yunkyung HONG ; Youngjeon LEE ; Jinyoung WON ; Kyu Tae CHANG ; Yonggeun HONG
Laboratory Animal Research 2012;28(1):1-9
Exercise training can improve strength and lead to adaptations in the skeletal muscle and nervous systems. Skeletal muscles can develop into two types: fast and slow, depending on the expression pattern of myosin heavy chain (MHC) isoforms. Previous studies reported that exercise altered the distribution of muscle fiber types. It is not currently known what changes in the expression of caveolins and types of muscle fiber occur in response to the intensity of exercise. This study determined the changes in expression of caveolins and MHC type after forced exercise in muscular and non-muscular tissues in rats. A control (Con) group to which forced exercise was not applied and an exercise (Ex) group to which forced exercise was applied. Forced exercise, using a treadmill, was introduced at a speed of 25 m/min for 30 min, 3 times/day (07:00, 15:00, 23:00). Homogenized tissues were applied to extract of total RNA for further gene analysis. The expression of caveolin-3 and MHC2a in the gastrocnemius muscle of female rats significantly increased in the Ex group compared with the Con group (P<0.05). Furthermore, in the gastrocnemius muscle of male rats, the expression of MHC2x was significantly different between the two groups (P<0.05). There was an increased expression in caveolin-3 and a slightly decreased expression in TGFbeta-1 in muscular tissues implicating caveolin-3 influences the expression of MHC isoforms and TGFbeta-1 expression. Eventually, it implicates that caveolin-3 has positive regulatory function in muscle atrophy induced by neural dysfunction with spinal cord injury or stroke.
Animals
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Caveolin 3
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Caveolins
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Female
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Humans
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Male
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Muscle, Skeletal
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Muscles
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Muscular Atrophy
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Myosin Heavy Chains
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Myosins
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Nervous System
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Protein Isoforms
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Rats
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RNA
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Spinal Cord Injuries
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Stroke
4.Acute gastrointestinal dilation in laboratory rhesus monkeys in the Korea National Primate Research Center.
Kyoung Min KIM ; Sang Rae LEE ; Kwon Sik CHANG ; Yong Hoon LEE ; Sung Woo KIM ; Kang Jin JUNG ; Youngjeon LEE ; Doo KIM ; Kyu Tae CHANG
Laboratory Animal Research 2012;28(3):217-221
Acute gastrointestinal dilation is a medical condition in which the stomach and intestine become overstretched by excessive gas content. In laboratory monkeys, cases of bloating involving gastrointestinal dilation are rarely seen, and the cause thereof is not clearly defined. Two rhesus monkeys in the Korea National Primate Research Center were found to suffer from acute gastrointestinal dilation. One of the monkeys showed severe gastric bloating after recovering from general anesthesia with isoflurane, where after it died suddenly. During necropsy, severe congestion of the lung was observed. The other monkey showed gastrointestinal dilation and died after treatment. During necropsy, severe dilation of the large intestine was observed. Severe congestion was detected in small and large intestines. Histopathologically, erythrocytes were found to fill the alveoli and alveolar capillaries of the lung. In stomach, epithelial cells were found to be sloughed from the mucosal layer, and erythrocytes were found to fill the blood vessels of the submucosal and mucosal layers. In small and large intestines, epithelial cells were also found to be sloughed from the mucosal layer, and inflammatory cells were found to have infiltrated in the submucosa (only large intestine) and mucosa. Microbiologically, Enterococcus faecalis and the pathogenic Staphylococcus haemolyticus, which do not form gas in the gastrointestinal tract, were detected in the gastrointestinal contents of both monkeys. These results suggest that the cause of the acute gastrointestinal dilation in these monkeys was not infection by gas-forming bacteria, but rather multiple factors such as diet, anesthesia, and excessive water consumption.
Anesthesia
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Anesthesia, General
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Bacteria
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Blood Vessels
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Capillaries
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Diet
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Drinking
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Enterococcus faecalis
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Epithelial Cells
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Erythrocytes
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Estrogens, Conjugated (USP)
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Gastrointestinal Contents
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Gastrointestinal Tract
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Haplorhini
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Intestine, Large
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Intestines
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Isoflurane
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Korea
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Lung
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Macaca mulatta
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Mucous Membrane
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Primates
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Staphylococcus haemolyticus
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Stomach
5.Synaptic loss and amyloid beta alterations in the rodent hippocampus induced by streptozotocin injection into the cisterna magna
Yujin AHN ; Jincheol SEO ; Junghyung PARK ; Jinyoung WON ; Hyeon-Gu YEO ; Keonwoo KIM ; Chang-Yeop JEON ; Jae-Won HUH ; Sang-Rae LEE ; Dong-Seok LEE ; Youngjeon LEE
Laboratory Animal Research 2020;36(2):134-139
To date, researchers have developed various animal models of Alzheimer’s disease (AD) to investigate its mechanisms and to identify potential therapeutic treatments. A widely recognized model that mimics the pathology of human sporadic AD involves intracerebroventricular (ICV) injection with streptozotocin (STZ). However, ICV injections are an invasive approach, which creates limitations in generalizing the results. In this study, we produced a rodent model of AD using STZ (3 mg/kg) injection via the cisterna magna (CM) once every week for 4 weeks, and analyzed at 4 weeks and 16 weeks after final injection. In the CM-STZ rodent model of AD, we observed increase in extracellular amyloid-beta (Aβ) deposition and decrease and abnormal morphology of post-synaptic protein, PSD95 in 16 weeks STZ-injected group. The model developed using our less-invasive method induced features of AD-like pathology, including significantly increased extracellular amyloid-beta deposition, and decreased synaptic protein in the hippocampus. These findings supporting the success of this alternative approach, and thus, we suggest this is a promising, less invasive model for use in future AD research.
6.Age-related Effects of Heroin on Gene Expression in the Hippocampus and Striatum of Cynomolgus Monkeys
Mi Ran CHOI ; Yeung-Bae JIN ; Sol Hee BANG ; Chang-Nim IM ; Youngjeon LEE ; Han-Na KIM ; Kyu-Tae CHANG ; Sang-Rae LEE ; Dai-Jin KIM
Clinical Psychopharmacology and Neuroscience 2020;18(1):93-108
Objective:
The aim of this study was to investigate differentially expressed genes and their functions in the hippocampus and striatum after heroin administration in cynomolgus macaques of different ages.
Methods:
Cynomolgus monkeys were divided by age as follows: 1 year (A1, n = 2); 3 to 4 years (A2, n = 2); 6 to 8 years (A3, n = 2); and older than 11 years (A4, n = 2). After heroin was injected intramuscularly into the monkeys (0.6 mg/kg), we performed large-scale transcriptome profiling in the hippocampus (H) and striatum (S) using RNA sequencing technology. Some genes were validated with real-time quantitative PCR.
Results:
In the hippocampus, the gene expression of A1H was similar to that of A4H, while the gene expression of A2H was similar to that of A3H. Genes associated with the mitogen-activated protein kinase signaling pathway (STMN1, FGF14, and MAPT) and -aminobutyric acid-ergic synapses (GABBR2 and GAD1) were differentially expressed among control and heroin-treated animals. Differential gene expression between A1S and A4S was the least significant, while differential gene expression between A3S and A2S was the most significant. Genes associated with the neurotrophin signaling pathway (NTRK1 and NGFR), autophagy (ATG5), and dopaminergic synapses (AKT1) in the striatum were differentially expressed among control and heroin-treated animals.
Conclusion
These results suggest that even a single heroin exposure can cause differential gene expression in the hippocampus and striatum of nonhuman primates at different ages.
7.Reference values of hematological and biochemical parameters in young-adult cynomolgus monkey (Macaca fascicularis) and rhesus monkey (Macaca mulatta) anesthetized with ketamine hydrochloride
Bon Sang KOO ; Dong Ho LEE ; Philyong KANG ; Kang Jin JEONG ; Sangil LEE ; Kijin KIM ; Youngjeon LEE ; Jae Won HUH ; Young Hyun KIM ; Sang Je PARK ; Yeung Bae JIN ; Sun Uk KIM ; Ji Su KIM ; Yeonghoon SON ; Sang Rae LEE
Laboratory Animal Research 2019;35(2):39-44
Nonhuman primate models are valuable in biomedical research. However, reference data for clinical pathology parameters in cynomolgus and rhesus monkeys are limited. In the present study, we established hematologic and biochemical reference intervals for healthy cynomolgus and rhesus monkeys anesthetized with ketamine hydrochloride. A total of 142 cynomolgus monkeys (28 males and 114 females) and 42 rhesus monkeys (22 males and 20 females) were selected and analyzed in order to examine reference intervals of 20 hematological and 16 biochemical parameters. The effects of sex were also investigated. Reference intervals for hematological and biochemical parameters were separately established by species (cynomolgus and rhesus) and sex (male and female). No sex-related differences were determined in erythrocyte-related parameters for cynomolgus and rhesus monkey housed in indoor laboratory conditions. Alkaline phosphatase and gamma glutamyltransferase were significantly lower in females than males in both cynomolgus and rhesus monkeys aged 48–96 months. The reference values for hematological and biochemical parameters established herein might provide valuable information for researchers using cynomolgus and rhesus monkeys in experimental conditions for biomedical studies.
8.XperCT-guided Intra-cisterna Magna Injection of Streptozotocin for Establishing an Alzheimer’s Disease Model Using the Cynomolgus Monkey (Macaca fascicularis)
Junghyung PARK ; Jinyoung WON ; Chang-Yeop JEON ; Kyung Seob LIM ; Won Seok CHOI ; Sung-hyun PARK ; Jincheol SEO ; Jiyeon CHO ; Jung Bae SEONG ; Hyeon-Gu YEO ; Keonwoo KIM ; Yu Gyeong KIM ; Minji KIM ; Kyung Sik YI ; Youngjeon LEE
Experimental Neurobiology 2022;31(6):409-418
Till date, researchers have been developing animal models of Alzheimer’s disease (AD) in various species to understand the pathological characterization and molecular mechanistic pathways associated with this condition in humans to identify potential therapeutic treatments. A widely recognized AD model that mimics the pathology of human AD involves the intracerebroventricular (ICV) injection with streptozotocin (STZ).However, ICV injection as an invasive approach has several limitations related to complicated surgical procedures. Therefore, in the present study, we created a customized stereotaxic frame using the XperCT-guided system for injecting STZ in cynomolgus monkeys, aiming to establish an AD model. The anatomical structures surrounding the cisterna magna (CM) were confirmed using CT/MRI fusion images of monkey brain with XperCT, the c-arm cone beam computed tomography. XperCT was used to determine the appropriate direction in which the needle tip should be inserted within the CM region. Cerebrospinal fluid (CSF) was collected to confirm the accurate target site when STZ was injected into the CM.Cynomolgus monkeys were administered STZ dissolved in artificial CSF once every week for 4 weeks via intracisterna magna (ICM) injection using XperCT-guided stereotactic system. The molecular mechanisms underlying the progression of STZ-induced AD pathology were analyzed two weeks after the final injection. The monkeys subjected to XperCT-based STZ injection via the ICM route showed features of AD pathology, including markedly enhanced neuronal loss, synaptic impairment, and tau phosphorylation in the hippocampus. These findings suggest a new approach for the construction of neurodegenerative disease models and development of therapeutic strategies.
9.Evaluation of fecal microbiomes associated with obesity in captive cynomolgus monkeys (Macaca fascicularis)
Bon Sang KOO ; Eun Ha HWANG ; Green KIM ; Hanseul OH ; Yeonghoon SON ; Dongho LEE ; Kyung Seob LIM ; Philyong KANG ; Sangil LEE ; Hwal Yong LEE ; Kang Jin JEONG ; Youngjeon LEE ; Seung Ho BAEK ; Chang Yeop JEON ; Sang Je PARK ; Young Hyun KIM ; Jae Won HUH ; Yeung Bae JIN ; Sun Uk KIM ; Sang Rae LEE ; Jung Joo HONG
Journal of Veterinary Science 2019;20(3):e19-
Microorganisms play important roles in obesity; however, the role of the gut microbiomes in obesity is controversial because of the inconsistent findings. This study investigated the gut microbiome communities in obese and lean groups of captive healthy cynomolgus monkeys reared under strict identical environmental conditions, including their diet. No significant differences in the relative abundance of Firmicutes, Bacteroidetes and Prevotella were observed between the obese and lean groups, but a significant difference in Spirochetes (p < 0.05) was noted. Microbial diversity and richness were similar, but highly variable results in microbial composition, diversity, and richness were observed in individuals, irrespective of their state of obesity. Distinct clustering between the groups was not observed by principal coordinate analysis using an unweighted pair group method. Higher sharedness values (95.81% ± 2.28% at the genus level, and 79.54% ± 5.88% at the species level) were identified among individual monkeys. This paper reports the association between the gut microbiome and obesity in captive non-human primate models reared under controlled environments. The relative proportion of Firmicutes and Bacteroidetes as well as the microbial diversity known to affect obesity were similar in the obese and lean groups of monkeys reared under identical conditions. Therefore, obesity-associated microbial changes reported previously appear to be associated directly with environmental factors, particularly diet, rather than obesity.
Bacteroidetes
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Diet
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Environment, Controlled
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Firmicutes
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Gastrointestinal Microbiome
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Haplorhini
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Macaca fascicularis
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Methods
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Microbiota
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Obesity
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Prevotella
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Primates
;
Spirochaetales
10.Abnormal Mitochondria in a Non-human Primate Model of MPTP-induced Parkinson's Disease: Drp1 and CDK5/p25 Signaling
Junghyung PARK ; Jincheol SEO ; Jinyoung WON ; Hyeon Gu YEO ; Yu Jin AHN ; Keonwoo KIM ; Yeung Bae JIN ; Bon Sang KOO ; Kyung Seob LIM ; Kang Jin JEONG ; Philyong KANG ; Hwal Yong LEE ; Seung Ho BAEK ; Chang Yeop JEON ; Jung Joo HONG ; Jae Won HUH ; Young Hyun KIM ; Sang Je PARK ; Sun Uk KIM ; Dong Seok LEE ; Sang Rae LEE ; Youngjeon LEE
Experimental Neurobiology 2019;28(3):414-424
Mitochondria continuously fuse and divide to maintain homeostasis. An impairment in the balance between the fusion and fission processes can trigger mitochondrial dysfunction. Accumulating evidence suggests that mitochondrial dysfunction is related to neurodegenerative diseases such as Parkinson's disease (PD), with excessive mitochondrial fission in dopaminergic neurons being one of the pathological mechanisms of PD. Here, we investigated the balance between mitochondrial fusion and fission in the substantia nigra of a non-human primate model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD. We found that MPTP induced shorter and abnormally distributed mitochondria. This phenomenon was accompanied by the activation of dynamin-related protein 1 (Drp1), a mitochondrial fission protein, through increased phosphorylation at S616. Thereafter, we assessed for activation of the components of the cyclin-dependent kinase 5 (CDK5) and extracellular signal-regulated kinase (ERK) signaling cascades, which are known regulators of Drp1(S616) phosphorylation. MPTP induced an increase in p25 and p35, which are required for CDK5 activation. Together, these findings suggest that the phosphorylation of Drp1(S616) by CDK5 is involved in mitochondrial fission in the substantia nigra of a non-human primate model of MPTP-induced PD.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
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Cyclin-Dependent Kinase 5
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Cyclin-Dependent Kinases
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Dopaminergic Neurons
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Homeostasis
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Mitochondria
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Mitochondrial Dynamics
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Neurodegenerative Diseases
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Parkinson Disease
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Phosphorylation
;
Phosphotransferases
;
Primates
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Substantia Nigra