Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, AL 35294.
Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, AL 35294
Proc Natl Acad Sci U S A. 2014 Jun 24;111(25):9289-94. doi: 10.1073/pnas.1403215111. Epub 2014 Jun 9.
Missense mutations in the leucine-rich repeat kinase 2 (LRRK2) gene can cause late-onset Parkinson disease. Past studies have provided conflicting evidence for the protective effects of LRRK2 knockdown in models of Parkinson disease as well as other disorders. These discrepancies may be caused by uncertainty in the pathobiological mechanisms of LRRK2 action. Previously, we found that LRRK2 knockdown inhibited proinflammatory responses from cultured microglia cells. Here, we report LRRK2 knockout rats as resistant to dopaminergic neurodegeneration elicited by intracranial administration of LPS. Such resistance to dopaminergic neurodegeneration correlated with reduced proinflammatory myeloid cells recruited in the brain. Additionally, adeno-associated virus-mediated transduction of human α-synuclein also resulted in dopaminergic neurodegeneration in wild-type rats. In contrast, LRRK2 knockout animals had no significant loss of neurons and had reduced numbers of activated myeloid cells in the substantia nigra. Although LRRK2 expression in the wild-type rat midbrain remained undetected under nonpathological conditions, LRRK2 became highly expressed in inducible nitric oxide synthase (iNOS)-positive myeloid cells in the substantia nigra in response to α-synuclein overexpression or LPS exposures. Our data suggest that knocking down LRRK2 may protect from overt cell loss by inhibiting the recruitment of chronically activated proinflammatory myeloid cells. These results may provide value in the translation of LRRK2-targeting therapeutics to conditions where neuroinflammation may underlie aspects of neuronal dysfunction and degeneration.
LRRK2 基因中的错义突变可导致迟发性帕金森病。过去的研究为 LRRK2 敲低在帕金森病模型以及其他疾病中的保护作用提供了相互矛盾的证据。这些差异可能是由于 LRRK2 作用的病理生物学机制不确定所致。此前，我们发现 LRRK2 敲低可抑制培养的小胶质细胞中的促炎反应。在这里，我们报告 LRRK2 基因敲除大鼠对脑内给予 LPS 引起的多巴胺能神经退行性变具有抗性。这种对多巴胺能神经退行性变的抗性与大脑中募集的促炎髓样细胞减少相关。此外，腺相关病毒介导的人α-突触核蛋白转导也可导致野生型大鼠的多巴胺能神经退行性变。相比之下，LRRK2 基因敲除动物的神经元没有明显丢失，黑质中的活化髓样细胞数量也减少。尽管在非病理条件下，野生型大鼠中脑的 LRRK2 表达仍未检测到，但在α-突触核蛋白过表达或 LPS 暴露时，LRRK2 在黑质中诱导型一氧化氮合酶（iNOS）阳性髓样细胞中高度表达。我们的数据表明，通过抑制慢性激活的促炎髓样细胞的募集，敲低 LRRK2 可能会防止明显的细胞丢失。这些结果可能为将 LRRK2 靶向治疗转化为神经炎症可能是神经元功能和变性某些方面的基础的疾病提供了价值。
