囊泡单胺转运体2的过表达可能阻止细胞溶质多巴胺产生神经毒性代谢物：一种治疗帕金森病的潜在神经保护疗法。
Overexpression of Vesicular Monoamine Transporter-2 may Block Neurotoxic Metabolites from Cytosolic Dopamine: a Potential Neuroprotective Therapy for Parkinson's Disease.
作者信息
Sulzer David, Zucca Fabio A, Zecca Luigi
机构信息
Molecular and Clinical Pharmacology, ICBM, Faculty of Medicine, University of Chile, Santiago,Chile.
Departments of Psychiatry, Neurology, Pharmacology, Columbia University, New York State 9 Psychiatric Institute, NY.
出版信息
Clin Pharmacol Transl Med. 2019;3(1):143-148. Epub 2019 May 6.
Abstract
The loss of nigrostriatal dopaminergic neurons containing neuromelanin underlies the motor symptoms of Parkinson's disease. Neuromelanin accumulation into autophagic lysosomes is evidence of ongoing cytosolic dopamine stress in these neurons during normal aging. The formation of neuromelanin is likely neuroprotective, as oxidation of cytosolic dopamine to quinones and aldehydes, as reviewed here, can produce a host of neurotoxic sequela. In addition to sequestration of dopamine and its metabolites in autophagic lysosomes, the uptake of dopamine into monoaminergic neurons mediated by vesicular monoamine transporter-2 (VMAT- 2), prevents dopamine oxidation. Dopamine is stable in monoaminergic vesicles due to their low pH, and thus overexpression of VMAT-2 may provide a target for potential neuroprotective therapy in Parkinson's disease.
摘要
含有神经黑色素的黑质纹状体多巴胺能神经元的丧失是帕金森病运动症状的基础。在正常衰老过程中，神经黑色素在自噬溶酶体中的积累是这些神经元中持续存在的胞质多巴胺应激的证据。神经黑色素的形成可能具有神经保护作用，因为如本文所述，胞质多巴胺氧化为醌和醛会产生一系列神经毒性后果。除了将多巴胺及其代谢产物隔离在自噬溶酶体中，由囊泡单胺转运体2（VMAT-2）介导的多巴胺进入单胺能神经元的摄取可防止多巴胺氧化。由于单胺能囊泡的低pH值，多巴胺在其中是稳定的，因此VMAT-2的过表达可能为帕金森病潜在的神经保护治疗提供一个靶点。
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