Triplett Judy C, Zhang Zhaoshu, Sultana Rukhsana, Cai Jian, Klein Jon B, Büeler Hansruedi, Butterfield David Allan
Department of Chemistry, University of Kentucky, Lexington, Kentucky, USA.
J Neurochem. 2015 Jun;133(5):750-65. doi: 10.1111/jnc.13039. Epub 2015 Mar 1.
Parkinson's disease (PD) is an age-related, neurodegenerative motor disorder characterized by progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta and presence of α-synuclein-containing protein aggregates. Mutations in the mitochondrial Ser/Thr kinase PTEN-induced kinase 1 (PINK1) are associated with an autosomal recessive familial form of early-onset PD. Recent studies have suggested that PINK1 plays important neuroprotective roles against mitochondrial dysfunction by phosphorylating and recruiting Parkin, a cytosolic E3 ubiquitin ligase, to facilitate elimination of damaged mitochondria via autophagy-lysosomal pathways. Loss of PINK1 in cells and animals leads to various mitochondrial impairments and oxidative stress, culminating in dopaminergic neuronal death in humans. Using a 2-D polyacrylamide gel electrophoresis proteomics approach, the differences in expressed brain proteome and phosphoproteome between 6-month-old PINK1-deficient mice and wild-type mice were identified. The observed changes in the brain proteome and phosphoproteome of mice lacking PINK1 suggest that defects in signaling networks, energy metabolism, cellular proteostasis, and neuronal structure and plasticity are involved in the pathogenesis of familial PD. Mutations in PINK1 are associated with an early-onset form of Parkinson's disease (PD). This study examines changes in the proteome and phosphoproteome of the PINK1 knockout mouse brain. Alterations were noted in several key proteins associated with: increased oxidative stress, aberrant cellular signaling, altered neuronal structure, decreased synaptic plasticity, reduced neurotransmission, diminished proteostasis networks, and altered metabolism. 14-3-3ε, 14-3-3 protein epsilon; 3-PGDH, phosphoglycerate dehydrogenase; ALDOA, aldolase A; APT1, acyl-protein thioesterase 1; CaM, calmodulin; CBR3, carbonyl reductase [NADPH] 3; ENO2, gamma-enolase; HPRT, hypoxanthine-guanine phosphoribosyltransferase; HSP70, heat-shock-related 70 kDa protein 2; IDHc, cytoplasmic isocitrate dehydrogenase [NADP+]; MAPK1, mitogen-activated protein kinase 1; MEK1, MAP kinase kinase 1; MDHc, cytoplasmic malate dehydrogenase; NFM, neurofilament medium polypeptide; NSF, N-ethylmaleimide-sensitive fusion protein; PHB, prohibitin; PINK1, PTEN-induced putative kinase 1; PPIaseA, peptidyl-prolyl cis-trans isomerase A; PSA2, proteasome subunit alpha type-2; TK, transketolase; VDAC-2, voltage-dependent anion-selective channel protein 2.
帕金森病（PD）是一种与年龄相关的神经退行性运动障碍，其特征是黑质致密部多巴胺能神经元进行性退化以及存在含α-突触核蛋白的蛋白质聚集体。线粒体丝氨酸/苏氨酸激酶PTEN诱导激酶1（PINK1）的突变与常染色体隐性遗传的早发性帕金森病家族形式相关。最近的研究表明，PINK1通过磷酸化并募集胞质E3泛素连接酶Parkin来发挥重要的神经保护作用，以对抗线粒体功能障碍，从而促进通过自噬-溶酶体途径清除受损线粒体。细胞和动物中PINK1的缺失会导致各种线粒体损伤和氧化应激，最终导致人类多巴胺能神经元死亡。使用二维聚丙烯酰胺凝胶电泳蛋白质组学方法，鉴定了6月龄PINK1缺陷小鼠和野生型小鼠之间脑蛋白质组和磷酸化蛋白质组的表达差异。缺乏PINK1的小鼠脑蛋白质组和磷酸化蛋白质组中观察到的变化表明，信号网络、能量代谢、细胞蛋白质稳态以及神经元结构和可塑性的缺陷参与了家族性帕金森病的发病机制。PINK1的突变与早发性帕金森病（PD）形式相关。本研究检测了PINK1基因敲除小鼠脑蛋白质组和磷酸化蛋白质组的变化。在与以下方面相关的几种关键蛋白质中发现了改变：氧化应激增加、细胞信号异常、神经元结构改变、突触可塑性降低、神经传递减少、蛋白质稳态网络受损以及代谢改变。14-3-3ε，14-3-3蛋白ε；3-PGDH，磷酸甘油酸脱氢酶；ALDOA，醛缩酶A；APT1，酰基蛋白硫酯酶1；CaM，钙调蛋白；CBR3，羰基还原酶[NADPH]3；ENO2，γ-烯醇化酶；HPRT，次黄嘌呤-鸟嘌呤磷酸核糖转移酶；HSP70，热休克相关70 kDa蛋白2；IDHc，胞质异柠檬酸脱氢酶[NADP+]；MAPK1，丝裂原活化蛋白激酶1；MEK1，丝裂原活化蛋白激酶激酶1；MDHc，胞质苹果酸脱氢酶；NFM，神经丝中型多肽；NSF，N-乙基马来酰亚胺敏感融合蛋白；PHB，抑制素；PINK1，PTEN诱导的假定激酶1；PPIaseA，肽基脯氨酰顺反异构酶A；PSA2，蛋白酶体α亚基-2；TK，转酮醇酶；VDAC-2，电压依赖性阴离子选择性通道蛋白2。
