神经退行性疾病的机制研究
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摘要
阿尔茨海默病( Alzheimer’s disease , AD)和帕金森氏病( Parkinson’s disease,PD)是两种最为常见的老年性神经退行性疾病。在这两种疾病中,患者脑内都对称性丢失了某些特定的神经元,并且这些特定的神经元丢失引起了患者的运动,感觉或是意识功能障碍。大部分的AD和PD病例都发生于晚年,表现为没有明显遗传特征的散发疾病,小部分则呈现为早期发生并与特定基因突变相关的遗传性病例。这两种疾病的病理发生机制尚不清楚,研究显示基因多态性、生活环境以及应激等多种因素都可以影响个体的易感性。到目前为止,还没有有效的药物可以治愈AD和PD。
Tau蛋白的过度磷酸化是AD的一个主要病理特征,而蛋白激酶A (protein kinase A, PKA)则是AD样过度磷酸化Tau蛋白的关键激酶之一。为探讨Tau蛋白的异常磷酸化的机制,我们在大鼠双侧海马内定位注射PKA的激动剂异丙去甲肾上腺素(isoproterenol, ISO)。免疫印迹结果显示,在海马内注射0.02μM ISO能激活PKA并能引起Tau蛋白在PHF-1和tau-1等疾病相关磷酸化位点的过度磷酸化。同时,大鼠脑内还表现出过氧化应激激活的相关指征,如过氧化物歧化酶的激活及malondialdehyde (MDA)的升高。腹腔内预注射褪黑素能部分逆转ISO引起的Tau蛋白过度磷酸化。低剂量的褪黑素(1mg/kg)连续注射4周即能逆转Tau蛋白PHF-1位点的异常磷酸化。而高剂量的褪黑素(10mg/kg)连续注射2周就能逆转PHF-1和tau-1两个位点的过度磷酸化。同时,连续2周注射10mg/kg的褪黑素可以明显地抑制ISO引起的PKA过度激活、过氧化物歧化酶的激活及MDA的升高。我们的研究表明,ISO引起Tau蛋白过度磷酸化的机制可能不仅仅只是通过激活PKA,还包括引起过氧化应激。褪黑素则能同时抑制激酶激活和过氧化应激,从而降低Tau蛋白过度磷酸化。
近年的研究表明,PINK1基因的突变能导致常染色体隐性PD,但PINK1的正常生理功能以及PINK1突变引起PD的病理机制尚不清楚。我们的研究表明,用RNA干扰的方法基因沉默果蝇的PINK1基因可以导致进行性发展的多巴胺能神经元丢失和果蝇小眼的退行性病变,而过表达人的PINK1基因可以逆转所有这些病理改变。同时,在果蝇体内表达人过氧化物歧化酶1也能抑制由PINK1基因沉默引起的神经退行性病变。给果蝇喂食抗氧化剂如过氧化物歧化酶1和维生素E也能明显地改善果蝇小眼的退行性改变。因此本研究提示果蝇的PINK1基因通过抑制过氧化损伤而起到保护神经元的作用,在因为PINK1基因突变而引起常染色体隐性PD的病人中,则可能由于正常PINK1基因功能的丢失而引起疾病。
尽管PD患者脑中选择性神经元死亡和Lewy小体形成的机制尚不清楚,但近年来,通过对早发家族性的PD病例的分析,已在PD的分子遗传学研究方面取得了重大成果。目前,已发现至少有六个基因与家族性PD相关,其中α-synuclein、uchL1和LRRK2基因的突变可导致常染色体显性遗传PD,parkin、PINK1和DJ-1基因的突变则导致常染色体隐性PD。我们的研究表明,parkin、PINK1和DJ-1形成E3泛素连接酶复合体(以下称PPD复合体)以促进parkin底物的泛素化及降解。去除PINK1或DJ-1会导致过量表达的parkin底物降解减少,聚集增加。而PD相关的parkin和PINK1突变能抑制这一E3泛素连接酶复合体的正常功能。我们的研究发现了一个全新的由parkin、PINK1和DJ-1等PD相关基因产物而组成的E3泛素连接酶复合体,揭示了这些疾病基因的相关性和相互作用性。同时我们还发现疾病基因突变能抑制正常的E3泛素连接酶功能,从而可能导致疾病。
Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common aging dependent neurodegenerative diseases. AD and PD are both characterized by a selective and symmetric loss of neurons in specific brain regions, resulting disruption of motor, sensory or cognitive nervous systems, eventually various severe disabilities of the affected individuals. Most cases of AD and PD occur sporadically and late in life, rare familial forms of these diseases are also identified. Studies of the familial forms of the diseases revealed number of mutations in different causative genes. The causes of sporadic cases of the diseases remain elusive. Genetic polymorphisms and/or environmental stresses are indicated to increase the vuleraibility of affected individuals. Currently, there is no cure for both AD and PD. Understanding the molecular mechanism of these dieases will be essential to design effective treatment stratatgies.
Hyperphosphorylation of microtubule-associated protein tau at specific sites is a key pathological furture of AD. Protein kinase A (PKA) is a crucial kinase to generate AD-like hyperphosphorylation of tua protein in the cell. In the study presented in Chapter 1, we found that injection of isoproterenol (ISO), a PKA specific activator, into hippocampus of rat brain induced PKA overactivation, activation of superoxide dismutase (SOD), elevation of malondialdehyde (MDA), and eventual tau hyperphosphorylation. The results suggest that ISO causes oxidative stress in rat brain. Pre-infusion of melatonin intraperitoneally partially reversed ISO-induced tau hyperphosphorylation. Furthermore, melatonin inhibits ISO-induced PKA activation, enhanced SOD activity, decreased the level of MDA in rat brain tissues. This study suggested that ISO likely induce abnormal hyperphosphorylation of tau via activation of PKA and increase of oxidative stress. Melatonin protects against ISO-induced tau hyperphosphorylation through suppression of both PKA overactivation and oxidative stress.
Mutations in the PINK1 gene are linked to autosomal recessive early onset familial form of PD. The physiological function of PINK1 and pathological abnormality of PD-associated PINK1 mutants are largely unknown. In studies presendeted in Chapeter 2, I show that inactivation of Drosophila PINK1 (dPINK1) using RNAi results in progressive loss of dopaminergic (DA) neurons and in ommatidial degeneration of the compound eye, which is rescued by expression of human PINK1 (hPINK1). Expression of human SOD1 suppresses neurodegeneration induced by dPINK1 inactivation. Moreover, treatment of dPINK1 RNAi flies with the antioxidants SOD and vitamin E significantly inhibits ommatidial degeneration. Thus, dPINK1 plays an essential role in maintaining neuronal survival by preventing neurons from undergoing oxidative stress, thereby suggesting a potential mechanism by which a reduction in PINK1 function leads to PD-associated neurodegeneration.
Mutations in parkin, the PTEN-induced kinase 1 (PINK1) and DJ-1 are individually linked to autosomal recessive early-onset familial forms of PD. Despite the fact that mutations in these genes cause the same disease, their functional relationships and how respective disease-associated mutations cause selective neuronal loss and Lewy body formation are largely unknown. In the study presented in Chapter 4, we demonstrate that parkin, PINK1 and DJ-1 form a complex to promote ubiquitination and degradation of parkin substrates, including parkin itself and synphilin-1. Genetic ablation of either PINK1 or DJ-1 resulted in decreased acute degradation and increased accumulation of parkin substrates. PD-pathogenic parkin and PINK1 mutations impair degradation activity of the complex. This study identifies a novel functional ubiquitin E3 ligase complex consisting of parkin, PINK1 and DJ-1 and suggests that PD-pathogenic parkin, PINK1, or DJ-1 mutations disrupt E3 ligase activity of the complex, which may constitute a mechanism underlying PD pathogenesis.
Tau蛋白的过度磷酸化是AD的一个主要病理特征,而蛋白激酶A (protein kinase A, PKA)则是AD样过度磷酸化Tau蛋白的关键激酶之一。为探讨Tau蛋白的异常磷酸化的机制,我们在大鼠双侧海马内定位注射PKA的激动剂异丙去甲肾上腺素(isoproterenol, ISO)。免疫印迹结果显示,在海马内注射0.02μM ISO能激活PKA并能引起Tau蛋白在PHF-1和tau-1等疾病相关磷酸化位点的过度磷酸化。同时,大鼠脑内还表现出过氧化应激激活的相关指征,如过氧化物歧化酶的激活及malondialdehyde (MDA)的升高。腹腔内预注射褪黑素能部分逆转ISO引起的Tau蛋白过度磷酸化。低剂量的褪黑素(1mg/kg)连续注射4周即能逆转Tau蛋白PHF-1位点的异常磷酸化。而高剂量的褪黑素(10mg/kg)连续注射2周就能逆转PHF-1和tau-1两个位点的过度磷酸化。同时,连续2周注射10mg/kg的褪黑素可以明显地抑制ISO引起的PKA过度激活、过氧化物歧化酶的激活及MDA的升高。我们的研究表明,ISO引起Tau蛋白过度磷酸化的机制可能不仅仅只是通过激活PKA,还包括引起过氧化应激。褪黑素则能同时抑制激酶激活和过氧化应激,从而降低Tau蛋白过度磷酸化。
近年的研究表明,PINK1基因的突变能导致常染色体隐性PD,但PINK1的正常生理功能以及PINK1突变引起PD的病理机制尚不清楚。我们的研究表明,用RNA干扰的方法基因沉默果蝇的PINK1基因可以导致进行性发展的多巴胺能神经元丢失和果蝇小眼的退行性病变,而过表达人的PINK1基因可以逆转所有这些病理改变。同时,在果蝇体内表达人过氧化物歧化酶1也能抑制由PINK1基因沉默引起的神经退行性病变。给果蝇喂食抗氧化剂如过氧化物歧化酶1和维生素E也能明显地改善果蝇小眼的退行性改变。因此本研究提示果蝇的PINK1基因通过抑制过氧化损伤而起到保护神经元的作用,在因为PINK1基因突变而引起常染色体隐性PD的病人中,则可能由于正常PINK1基因功能的丢失而引起疾病。
尽管PD患者脑中选择性神经元死亡和Lewy小体形成的机制尚不清楚,但近年来,通过对早发家族性的PD病例的分析,已在PD的分子遗传学研究方面取得了重大成果。目前,已发现至少有六个基因与家族性PD相关,其中α-synuclein、uchL1和LRRK2基因的突变可导致常染色体显性遗传PD,parkin、PINK1和DJ-1基因的突变则导致常染色体隐性PD。我们的研究表明,parkin、PINK1和DJ-1形成E3泛素连接酶复合体(以下称PPD复合体)以促进parkin底物的泛素化及降解。去除PINK1或DJ-1会导致过量表达的parkin底物降解减少,聚集增加。而PD相关的parkin和PINK1突变能抑制这一E3泛素连接酶复合体的正常功能。我们的研究发现了一个全新的由parkin、PINK1和DJ-1等PD相关基因产物而组成的E3泛素连接酶复合体,揭示了这些疾病基因的相关性和相互作用性。同时我们还发现疾病基因突变能抑制正常的E3泛素连接酶功能,从而可能导致疾病。
Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common aging dependent neurodegenerative diseases. AD and PD are both characterized by a selective and symmetric loss of neurons in specific brain regions, resulting disruption of motor, sensory or cognitive nervous systems, eventually various severe disabilities of the affected individuals. Most cases of AD and PD occur sporadically and late in life, rare familial forms of these diseases are also identified. Studies of the familial forms of the diseases revealed number of mutations in different causative genes. The causes of sporadic cases of the diseases remain elusive. Genetic polymorphisms and/or environmental stresses are indicated to increase the vuleraibility of affected individuals. Currently, there is no cure for both AD and PD. Understanding the molecular mechanism of these dieases will be essential to design effective treatment stratatgies.
Hyperphosphorylation of microtubule-associated protein tau at specific sites is a key pathological furture of AD. Protein kinase A (PKA) is a crucial kinase to generate AD-like hyperphosphorylation of tua protein in the cell. In the study presented in Chapter 1, we found that injection of isoproterenol (ISO), a PKA specific activator, into hippocampus of rat brain induced PKA overactivation, activation of superoxide dismutase (SOD), elevation of malondialdehyde (MDA), and eventual tau hyperphosphorylation. The results suggest that ISO causes oxidative stress in rat brain. Pre-infusion of melatonin intraperitoneally partially reversed ISO-induced tau hyperphosphorylation. Furthermore, melatonin inhibits ISO-induced PKA activation, enhanced SOD activity, decreased the level of MDA in rat brain tissues. This study suggested that ISO likely induce abnormal hyperphosphorylation of tau via activation of PKA and increase of oxidative stress. Melatonin protects against ISO-induced tau hyperphosphorylation through suppression of both PKA overactivation and oxidative stress.
Mutations in the PINK1 gene are linked to autosomal recessive early onset familial form of PD. The physiological function of PINK1 and pathological abnormality of PD-associated PINK1 mutants are largely unknown. In studies presendeted in Chapeter 2, I show that inactivation of Drosophila PINK1 (dPINK1) using RNAi results in progressive loss of dopaminergic (DA) neurons and in ommatidial degeneration of the compound eye, which is rescued by expression of human PINK1 (hPINK1). Expression of human SOD1 suppresses neurodegeneration induced by dPINK1 inactivation. Moreover, treatment of dPINK1 RNAi flies with the antioxidants SOD and vitamin E significantly inhibits ommatidial degeneration. Thus, dPINK1 plays an essential role in maintaining neuronal survival by preventing neurons from undergoing oxidative stress, thereby suggesting a potential mechanism by which a reduction in PINK1 function leads to PD-associated neurodegeneration.
Mutations in parkin, the PTEN-induced kinase 1 (PINK1) and DJ-1 are individually linked to autosomal recessive early-onset familial forms of PD. Despite the fact that mutations in these genes cause the same disease, their functional relationships and how respective disease-associated mutations cause selective neuronal loss and Lewy body formation are largely unknown. In the study presented in Chapter 4, we demonstrate that parkin, PINK1 and DJ-1 form a complex to promote ubiquitination and degradation of parkin substrates, including parkin itself and synphilin-1. Genetic ablation of either PINK1 or DJ-1 resulted in decreased acute degradation and increased accumulation of parkin substrates. PD-pathogenic parkin and PINK1 mutations impair degradation activity of the complex. This study identifies a novel functional ubiquitin E3 ligase complex consisting of parkin, PINK1 and DJ-1 and suggests that PD-pathogenic parkin, PINK1, or DJ-1 mutations disrupt E3 ligase activity of the complex, which may constitute a mechanism underlying PD pathogenesis.
引文
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