Age-associated sex difference in the expression of mitochondria-based redox sensitive proteins and effect of pioglitazone in nonhuman primate brain.
Age-associated sex difference in the expression of mitochondria-based redox sensitive proteins and effect of pioglitazone in nonhuman primate brain.
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DOI：
10.1186/s13293-023-00551-6
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发表时间：
2023-09-28
影响因子：
7.9
通讯作者：
Elsworth, John D.
中科院分区：
文献类型：
--
作者：
Jamwal, Sumit;Blackburn, Jennifer K.;Elsworth, John D.
对氧磷酶2（PON 2）和神经元解偶联蛋白（UCP 4和UCP 5）具有抗氧化、抗凋亡活性，并使活性氧在线粒体中的积累最小化。虽然年龄和性别是与氧化应激相关的几种疾病的风险因素，但没有研究探讨过灵长类动物大脑中PON 2亚型，UCP 4和UCP 5的年龄和性别依赖性表达，或者确定了体内激活UCP 4和UCP 5的药物。临床前研究表明，过氧化物酶体增殖物激活受体γ激动剂，吡格列酮（PIO），可以是神经保护，虽然负责的机制尚不清楚。我们以前的研究表明，吡格列酮激活灵长类动物脑中的PON 2，我们假设吡格列酮也诱导UCP 4/5。本研究旨在阐明PON 2亚型UCP 4和UCP 5的年龄和性别依赖性表达，以及研究全身PIO治疗对灵长类动物脑中UCP 4和UCP 5表达的影响。采用Western blot技术检测UCP 4和UCP 5在非洲绿色猴黑质和纹状体中的表达，并分析其与年龄和性别的关系。此外，我们检测了每日口服吡格列酮（5 mg/kg/天）或溶剂1周或3周对成年雄性猴黑质和纹状体中UCP 4和UCP 5表达的影响。使用LC-MS测定血浆和脑脊液（CSF）中的PIO水平。我们发现年轻猴子的纹状体和黑质中PON 2亚型、UCP 4和UCP 5的表达没有性别差异。然而，我们发现，成年雌性猴子表现出更大的表达比雄性黑质和纹状体的PON 2亚型。我们的数据还显示，成年雄性猴子表现出更大的表达UCP 4和UCP 5比女性在黑质，但不是在纹状体。PIO增加UCP 4和UCP 5的表达在黑质和纹状体在1周，但在治疗3周后，这种激活已经消退。我们的研究结果表明，PON 2，UCP 4和UCP 5的表达具有性别，年龄和区域依赖性。这些数据建立了灵长类动物脑中PPARγ、PON 2、UCP 4和UCP 5之间的生物化学联系，并证明PON 2、UCP 4和UCP 5可以在体内被神经刺激，揭示了观察到的吡格列酮诱导的神经保护作用的新机制。我们预计，这些结果将有助于开发新的神经保护治疗帕金森病和其他中枢神经系统疾病。帕金森病（PD）在女性中比男性更不常见，这可能与女性体内高水平雌激素的保护作用有关，雌激素可维持脑线粒体中神经保护蛋白的活性。我们以前的工作表明，对氧磷酶-2（PON 2），解偶联蛋白-4（UCP 4）和解偶联蛋白-5（UCP 5）在维持PD中丢失的脑多巴胺神经元的健康方面起着至关重要的作用。这项工作验证了雌性灵长类动物大脑比雄性表达更高水平的这些蛋白质的假设。此外，这项研究还调查了雌激素是否调节这些因子的表达，以及它们是否可以在以后的生活中被激活，以在PD症状通常出现时保护多巴胺神经元。结果表明，在青春期前，当女性雌激素水平相对较低时，男性和女性之间的PON 2，UCP 4，UCP 5脑水平没有差异，但在成年时，在与PD相关的区域，女性PON 2比男性高3倍，与PON 2的雌激素激活一致。早期的研究表明，吡格列酮可以在几种不利的大脑条件下具有神经保护作用，尽管其机制尚不清楚。目前的研究表明，吡格列酮在灵长类动物脑中瞬时激活约两倍的PON 2，UCP 4，UCP 5的表达，表明它们参与了药物的神经保护特性。总的来说，目前的数据为进一步研究激活保护因子提供了动力，这些保护因子改变了线粒体的动力学和功能，从而改善了对多种疾病的理解和治疗。PON 2、UCP 4和UCP 5具有抗氧化、抗凋亡活性，并使线粒体中活性氧的积累最小化。PON 2亚型在成年NHP的STR和SN区的表达存在性别差异，女性的表达水平较高。UCP 4和UCP 5在NHPs SN区的表达存在性别差异，男性表达水平较高。吡格列酮是第一个在STR和SN区域诱导UCP 4和UCP 5体内表达的药物。
Paraoxonase 2 (PON2) and neuronal uncoupling proteins (UCP4 and UCP5) possess antioxidant, anti-apoptotic activities and minimize accumulation of reactive oxygen species in mitochondria. While age and sex are risk factors for several disorders that are linked with oxidative stress, no study has explored the age- and sex-dependent expression of PON2 isoforms, UCP4 and UCP5 in primate brain or identified a drug to activate UCP4 and UCP5 in vivo. Preclinical studies suggest that the peroxisome proliferator-activated receptor gamma agonist, pioglitazone (PIO), can be neuroprotective, although the mechanism responsible is unclear. Our previous studies demonstrated that pioglitazone activates PON2 in primate brain and we hypothesized that pioglitazone also induces UCP4/5. This study was designed to elucidate the age- and sex-dependent expression of PON2 isoforms, UCP4 and UCP5, in addition to examining the impact of systemic PIO treatment on UCP4 and UCP5 expression in primate brain. Western blot technique was used to determine the age- and sex-dependent expression of UCP4 and UCP5 in substantia nigra and striatum of African green monkeys. In addition, we tested the impact of daily oral pioglitazone (5 mg/kg/day) or vehicle for 1 or 3 weeks on expression of UCP4 and UCP5 in substantia nigra and striatum in adult male monkeys. PIO levels in plasma and cerebrospinal fluid (CSF) were determined using LC–MS. We found no sex-based difference in the expression of PON2 isoforms, UCP4 and UCP5 in striatum and substantia nigra of young monkeys. However, we discovered that adult female monkeys exhibit greater expression of PON2 isoforms than males in substantia nigra and striatum. Our data also revealed that adult male monkeys exhibit greater expression of UCP4 and UCP5 than females in substantia nigra but not in striatum. PIO increased UCP4 and UCP5 expression in substantia nigra and striatum at 1 week, but after 3 weeks of treatment this activation had subsided. Our findings demonstrate a sex-, age- and region-dependent profile to the expression of PON2, UCP4 and UCP5. These data establish a biochemical link between PPARγ, PON2, UCP4 and UCP5 in primate brain and demonstrate that PON2, UCP4 and UCP5 can be pharmacologically stimulated in vivo, revealing a novel mechanism for observed pioglitazone-induced neuroprotection. We anticipate that these outcomes will contribute to the development of novel neuroprotective treatments for Parkinson’s disease and other CNS disorders. Parkinson’s disease (PD) is less common in women than men, which may be related to the protective effect of high levels of estrogens in women that maintain the activity of neuroprotective proteins in brain mitochondria. Our previous work suggests that paraoxonase-2 (PON2), uncoupling protein-4 (UCP4) and uncoupling protein-5 (UCP5) play vital roles in maintaining the health of brain dopamine neurons that are lost in PD. This work tested the hypothesis that female primate brains expresses higher levels of these proteins than males. In addition, this research investigated whether estrogen regulates the expression these factors and whether they can be pharmacologically activated later in life to protect dopamine neurons at a time when symptoms of PD typically emerge. The results indicate that before puberty when estrogen levels in females are relatively low, there is no difference in PON2, UCP4, UCP5 brain levels between males and females, but in adults PON2 is up to 3 × higher in females compared with males in regions relevant to PD, consistent with estrogen activation of PON2. Earlier studies have shown that pioglitazone can be neuroprotective in several adverse brain conditions, although the mechanism is not clear. The current research demonstrates that pioglitazone transiently activates by about twofold the expression of PON2, UCP4, UCP5 in vivo in primate brain, suggesting their involvement in the neuroprotective properties of the drug. Overall, the current data provides impetus for further work on activating protective factors that alter mitochondrial dynamics and function, leading to improved understanding and treatment of multiple diseases. PON2, UCP4 and UCP5 possess antioxidant, anti-apoptotic activities and minimize reactive oxygen species accumulation in mitochondria. Age-associated sex difference exists in expression of PON2 isoforms in adult STR and SN region of NHPs with higher levels found in females. Age-associated sex difference exists in expression of UCP4 and UCP5 in SN region of NHPs with higher levels found in males. Pioglitazone is first drug to induce in vivo expression of UCP4 and UCP5 in STR and SN regions.
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在男性和女性非洲绿猴中，PON2同工型的表达在大脑区域之间有所不同。
影响因子：
7.4
作者：
Jamwal S;Blackburn JK;Elsworth JD
通讯作者：
Elsworth JD
影响因子：
5.3
作者：
Blackburn, Jennifer K.;Curry, Daniel W.;Elsworth, John D.
通讯作者：
Elsworth, John D.
影响因子：
4.7
作者：
Conti, B;Sugama, S;Bartfai, T
通讯作者：
Bartfai, T
影响因子：
4.8
作者：
Horvath, TL;Diano, S;Redmond, DE
通讯作者：
Redmond, DE
影响因子：
17.8
作者：
Hass DT;Barnstable CJ
通讯作者：
Barnstable CJ