Dues Dylan J, Ma Yue, Nguyen An Phu Tran, Offerman Alina V, Beddows Ian, Moore Darren J
Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USA.
Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, USA.
Neurobiol Dis. 2023 Nov;188. doi: 10.1016/j.nbd.2023.106338. Epub 2023 Oct 29.
Leucine-rich repeat kinase 2 (LRRK2) and α-synuclein share enigmatic roles in the pathobiology of Parkinson's disease (PD). mutations are a common genetic cause of PD which, in addition to neurodegeneration, often present with abnormal deposits of α-synuclein in the form of Lewy-related pathology. As Lewy-related pathology is a prominent neuropathologic finding in sporadic PD, the relationship between LRRK2 and α-synuclein has garnered considerable interest. However, whether and how LRRK2 might influence the accumulation of Lewy-related pathology remains poorly understood. Through stereotactic injection of mouse α-synuclein pre-formed fibrils (PFF), we modeled the spread of Lewy-related pathology within forebrain regions where LRRK2 is most highly expressed. The impact of genotype on the formation of α-synuclein inclusions was evaluated at 1-month post-injection. Neither deletion of nor G2019S LRRK2 knockin appreciably altered the burden of α-synuclein pathology at this early timepoint. These observations fail to provide support for a robust pathophysiologic interaction between LRRK2 and α-synuclein in the forebrain . There was, however, a modest reduction in microglial activation induced by PFF delivery in the hippocampus of knockout mice, suggesting that LRRK2 may contribute to α-synuclein-induced neuroinflammation. Collectively, our data indicate that the pathological accumulation of α-synuclein in the mouse forebrain is largely independent of LRRK2.
富含亮氨酸重复激酶2（LRRK2）和α-突触核蛋白在帕金森病（PD）的病理生物学中具有神秘作用。LRRK2突变是PD常见的遗传病因，除神经退行性变外，常伴有以路易体相关病理形式存在的α-突触核蛋白异常沉积。由于路易体相关病理是散发性PD突出的神经病理学表现，LRRK2与α-突触核蛋白之间的关系备受关注。然而，LRRK2是否以及如何影响路易体相关病理的积累仍知之甚少。通过立体定向注射小鼠α-突触核蛋白预形成纤维（PFF），我们模拟了路易体相关病理在LRRK2表达最高的前脑区域内的传播。在注射后1个月评估LRRK2基因型对α-突触核蛋白包涵体形成的影响。在这个早期时间点，LRRK2基因敲除和G2019S LRRK2基因敲入均未明显改变α-突触核蛋白病理负担。这些观察结果不支持LRRK2与前脑α-突触核蛋白之间存在强大的病理生理相互作用。然而，在LRRK2基因敲除小鼠的海马中，由PFF递送诱导的小胶质细胞激活有适度降低，这表明LRRK2可能促成α-突触核蛋白诱导的神经炎症。总体而言，我们的数据表明小鼠前脑中α-突触核蛋白的病理积累在很大程度上独立于LRRK2。
