Mukhida K, Kobayashi N R, Mendez I
Cell Restoration Laboratory, 12th Floor, Department of Anatomy, Dalhousie University, Sir Charles Tupper Medical Building, 5850 College Street, Halifax, Nova Scotia, Canada B3H 4H7.
Med Hypotheses. 2005;64(6):1120-3. doi: 10.1016/j.mehy.2004.12.020.
Recently, loss-of-function mutations of parkin have been identified as being causally related to autosomal recessive juvenile parkinsonism, the most common form of familial Parkinson's disease. In addition to functioning as an E3 ubiquitin ligase that facilitates the proteasomal degradation of proteins with abnormal conformations, parkin protects dopaminergic neurons from oxidative stress-mediated death by regulating mitochondrial function. Parkin is expressed throughout the brain in a variety of functional and neurochemical systems. We propose that parkin's role in protecting neurons from oxidative stress may extend beyond the nigrostriatal system to include neurons in other regions of the central nervous system. This is relevant for therapeutic strategies for brain and spinal cord injury because oxidative stress leading to lipid peroxidation and protein and nucleic acid oxidation is a significant cause of secondary injury and thus neuronal death following traumatic injuries to the central nervous system. A novel model system to verify the process of oxidative stress as a causative factor in trauma-induced secondary injury mechanisms would be to induce traumatic brain and spinal cord injury in parkin-null mice. This is expected to provide the proof-of-principle that a cascade of oxidative stress is a causal event leading to secondary neuronal injury, that parkin functions outside of the dopaminergic system to protect other neurons from oxidative stress, and that antioxidant pharmacotherapy is a rational therapeutic approach to decrease trauma-induced neuronal injury.
最近，已确定帕金森蛋白的功能丧失突变与常染色体隐性少年帕金森病存在因果关系，这是家族性帕金森病最常见的形式。除了作为一种E3泛素连接酶促进蛋白酶体对异常构象蛋白质的降解外，帕金森蛋白还通过调节线粒体功能来保护多巴胺能神经元免受氧化应激介导的死亡。帕金森蛋白在大脑中多种功能和神经化学系统中均有表达。我们推测，帕金森蛋白在保护神经元免受氧化应激方面的作用可能不仅限于黑质纹状体系统，还包括中枢神经系统其他区域的神经元。这与脑和脊髓损伤的治疗策略相关，因为氧化应激导致脂质过氧化以及蛋白质和核酸氧化是继发性损伤的重要原因，也是中枢神经系统创伤性损伤后神经元死亡的原因。一种验证氧化应激过程作为创伤性继发性损伤机制致病因素的新型模型系统，是在帕金森蛋白缺失的小鼠中诱导创伤性脑和脊髓损伤。这有望提供原理证明，即一系列氧化应激是导致继发性神经元损伤的因果事件，帕金森蛋白在多巴胺能系统之外发挥作用以保护其他神经元免受氧化应激，并且抗氧化药物治疗是减少创伤性神经元损伤的合理治疗方法。
