Department of Neurology, Keio University School of Medicine, Japan.
Brain Res. 2011 Mar 25;1382:109-17. doi: 10.1016/j.brainres.2011.01.056. Epub 2011 Jan 27.
Parkinson's disease (PD), which is characterized by degeneration of mesencephalic dopaminergic neurons of unclear etiology, is primarily an age-related neurodegenerative disorder, while the normal process of aging is also known to decrease the number of dopaminergic neurons in the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA). However, no consensus exists regarding how advancing age may predispose the dopaminergic system to PD. The Klotho-insufficient (klotho) mouse exhibits a syndrome that resembles human aging. Recent studies have revealed that abnormal activation of vitamin D is the major cause of this phenotype. In this study, we examined mesencephalic dopaminergic neurons of klotho mice and identified tyrosine hydroxylase-positive neurons in the SNc and VTA, and found that levels of striatal dopamine were significantly decreased with aging in klotho mice. Notably, these phenotypes were rescued by vitamin D restriction, suggesting that abnormal activation of vitamin D due to Klotho insufficiency leads to degeneration of the dopaminergic system. The present study provides new insights into the pathology of age-related degeneration of dopaminergic neurons possibly related to Klotho-mediated regulation of vitamin D.
帕金森病（PD）的特征是中脑多巴胺能神经元退化，其病因不明，主要是一种与年龄相关的神经退行性疾病，而衰老的正常过程也已知会减少黑质致密部（SNc）和腹侧被盖区（VTA）中的多巴胺能神经元数量。然而，目前尚不清楚随着年龄的增长如何使多巴胺能系统易患 PD。Klotho 不足（klotho）小鼠表现出一种类似于人类衰老的综合征。最近的研究表明，维生素 D 的异常激活是这种表型的主要原因。在这项研究中，我们检查了 klotho 小鼠的中脑多巴胺能神经元，并鉴定了 SNc 和 VTA 中的酪氨酸羟化酶阳性神经元，发现 klotho 小鼠的纹状体多巴胺水平随着年龄的增长而显著下降。值得注意的是，这些表型通过限制维生素 D 得到挽救，这表明由于 Klotho 不足导致的维生素 D 异常激活导致多巴胺能系统的退化。本研究为与 Klotho 介导的维生素 D 调节相关的可能与年龄相关的多巴胺能神经元退化的病理学提供了新的见解。
