The anti-aging protein klotho alleviates injury of nigrostriatal dopaminergic pathway in 6-hydroxydopamine rat model of Parkinson's disease: Involvement of PKA/CaMKII/CREB signaling

Baluchnejadmojarad, Tourandokht; Eftekhari, Seyed-Mohammad; Jamali-Raeufy, Nida; Haghani, Sobhan; Zeinali, Hossein; Roghani, Mehrdad

doi:10.1016/j.exger.2017.10.023

Cited by 48 publications

(25 citation statements)

References 49 publications

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“…Specifically, in the development of PD, free radicals interact with several proteins involved in the pathology of PD (such as α-synuclein, and tau protein) and contribute to neuronal damage [10] , [11] , [12] . Multiple signaling pathways, including phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) and protein kinase A/cAMP response element-binding protein (PKA/CREB) pathways, are involved in the dopaminergic cell damage mediated by oxidative stress [8] , [13] , [14] . Oxidative stress can act as an initial trigger or is involved in the development of PD.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of phosphodiesterase 4 by FCPR16 protects SH-SY5Y cells against MPP+-induced decline of mitochondrial membrane potential and oxidative stress

Zhong

Huang

et al. 2018

Redox Biology

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Phosphodiesterase 4 (PDE4) is a promising target for the treatment of Parkinson's disease (PD). However, the underlying mechanism has not yet been well elucidated. Additionally, most of current PDE4 inhibitors produce severe nausea and vomiting response in patients, which limit their clinical application. FCPR16 is a novel PDE4 inhibitor with little emetic potential. In the present study, the neuroprotective effect and underlying mechanism of FCPR16 against cellular apoptosis induced by 1-methyl-4-phenylpyridinium (MPP+) were examined in SH-SY5Y cells. FCPR16 (12.5–50 μM) dose-dependently reduced MPP+-induced loss of cell viability, accompanied by reductions in nuclear condensation and lactate dehydrogenase release. The level of cleaved caspase 3 and the ratio of Bax/Bcl-2 were also decreased after treatment with FCPR16 in MPP+-treated cells. Furthermore, FCPR16 (25 μM) significantly suppressed the accumulation of reactive oxygen species (ROS), prevented the decline of mitochondrial membrane potential (Δψm) and attenuated the expression of malonaldehyde level. Further studies disclosed that FCPR16 enhanced the levels of cAMP and the exchange protein directly activated by cAMP (Epac) in SH-SY5Y cells. Western blotting analysis revealed that FCPR16 increased the phosphorylation of cAMP response element-binding protein (CREB) and protein kinase B (Akt) down-regulated by MPP+ in SH-SY5Y cells. Moreover, the inhibitory effects of FCPR16 on the production of ROS and Δψm loss could be blocked by PKA inhibitor H-89 and Akt inhibitor KRX-0401. Collectively, these results suggest that FCPR16 attenuates MPP+-induced dopaminergic degeneration via lowering ROS and preventing the loss of Δψm in SH-SY5Y cells. Mechanistically, cAMP/PKA/CREB and Epac/Akt signaling pathways are involved in these processes. Our findings indicate that FCPR16 is a promising pre-clinical candidate for the treatment of PD and possibly other oxidative stress-related neuronal diseases.

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Section: Introductionmentioning

confidence: 99%

Inhibition of phosphodiesterase 4 by FCPR16 protects SH-SY5Y cells against MPP+-induced decline of mitochondrial membrane potential and oxidative stress

Zhong

Huang

et al. 2018

Redox Biology

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“…In animal experiments, overexpression of Klotho protein delays aging and prolongs life span ( 10 , 11 ). In addition, it has previously been demonstrated that Klotho protein increases the ability of cells to remove reactive oxygen species (ROS) ( 12 ). In cell culture experiments and transgenic mice, it was also demonstrated that Klotho protein enhances the resistance of cells to ROS and prolongs the life span ( 13 ).…”

Section: Introductionmentioning

confidence: 99%

Aerobic exercise‑stimulated Klotho upregulation extends life span by attenuating the excess production of reactive oxygen species in the brain and kidney

Luan

et al. 2018

Exp Ther Med

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Aerobic exercise induces many adaptive changes in the whole body and improves metabolic characteristics. Klotho, an anti-aging gene, is mainly expressed in the brain and kidney. The roles of Klotho in the brain and kidney during aerobic exercise remain largely unknown. The present study aimed to determine whether aerobic exercise could influence the expression of Klotho, decrease reactive oxygen species (ROS) and prolong life span. Sprague Dawley rats were exercised on a motor treadmill. Klotho mRNA and protein expression levels in rat brain and kidney tissues were examined using reverse transcription-quantitative polymerase chain reaction and western blotting, respectively. ROS production was detected following intermittent aerobic exercise (IAE) or continuous aerobic exercise (CAE). Kaplan-Meier curve analysis demonstrated that aerobic exercise significantly improved rat survival (P<0.001). The ROS levels in rat brain and kidney tissues were decreased in the aerobic exercise groups compared with the control group (P<0.05). In addition, Klotho mRNA and protein expression levels were increased significantly following aerobic exercise compared with controls (P<0.05). There was no significant difference between the IAE and CAE groups in any experiments (P>0.05). These results suggest that aerobic exercise-stimulated Klotho upregulation extends the life span by attenuating the excess production of ROS in the brain and kidney. As Klotho exhibits a potential anti-aging effect, promoting Klotho expression through aerobic exercise may be a novel approach for the prevention and treatment of aging and aging-related diseases.

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“…Recent work on Klotho's functions in the CNS, performed by us and by others, demonstrated that Klotho can combat processes associated with neurodegeneration through diverse mechanisms. Klotho fosters survival of hippocampal [9,10], dopaminergic [11,12] and cortical neurons [13] and cerebellar granule cells; and counteracts oxidative stress [4]. Klotho enhances oligodendrocyte differentiation and maturation in vitro [14], and enhances re-myelination in vivo in the cuprizone-induced demyelination model of multiple sclerosis (MS) [15].…”

Section: Introductionmentioning

confidence: 99%

Identification of the cleavage sites leading to the shed forms of human and mouse anti-aging and cognition-enhancing protein Klotho

Chen

et al. 2020

PLoS ONE

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Klotho is an age-extending, cognition-enhancing protein found to be down-regulated in aged mammals when age-related diseases start to appear. Low levels of Klotho occur in neurodegenerative diseases, kidney disease and many cancers. Many normal and pathologic processes involve the proteolytic shedding of membrane proteins. Transmembrane (TM) Klotho contains two homologous domains, KL1 and KL2 with homology to glycosidases. After shedding by ADAM 10 and 17, a shed Klotho isoform is released into serum and urine by the kidney, and into the CSF by the choroid plexus. We previously reported that human Klotho contains two major cleavage sites. However, the exact cleavage site responsible for the cleavage between the KL1 and KL2 domains remains unknown for the human Klotho, and both sites are unknown for mouse Klotho. In this study, we aimed to identify the cleavage sites leading to the shed forms of human and mouse Klotho. Mutations in the region close to the TM domain of mouse Klotho result in the reduced shedding of the 130 kD (KL1 +KL2) and 70 kD (KL1) fragments, suggesting that the cleavage site lies within the mutated region. We further identified the cleavage sites responsible for the cleavage between KL1 and KL2 of human and mouse Klotho. Moreover, mutated Klotho proteins have similar subcellular localization patterns as wild type Klotho. Finally, in an FGF23 functional assay, all Klotho mutants with a nine amino acid deletion can also function as an FGFR1 co-receptor for FGF23 signaling, however, the signaling activity was greatly reduced. The study provides new and important information on Klotho shedding, and paves the way for studies aimed to distinguish between the distinct roles of the various isoforms of Klotho.

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The anti-aging protein klotho alleviates injury of nigrostriatal dopaminergic pathway in 6-hydroxydopamine rat model of Parkinson's disease: Involvement of PKA/CaMKII/CREB signaling

Cited by 48 publications

References 49 publications

Inhibition of phosphodiesterase 4 by FCPR16 protects SH-SY5Y cells against MPP+-induced decline of mitochondrial membrane potential and oxidative stress

Inhibition of phosphodiesterase 4 by FCPR16 protects SH-SY5Y cells against MPP+-induced decline of mitochondrial membrane potential and oxidative stress

Aerobic exercise‑stimulated Klotho upregulation extends life span by attenuating the excess production of reactive oxygen species in the brain and kidney

Identification of the cleavage sites leading to the shed forms of human and mouse anti-aging and cognition-enhancing protein Klotho

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