Lunn Michaela O, Rousso Christopher, Tomlinson Julianna J, Brown Earl G, Schlossmacher Michael G
Program in Neuroscience, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.
PLoS One. 2025 Jun 5;20(6):e0325248. doi: 10.1371/journal.pone.0325248. eCollection 2025.
Variants at the leucine-rich repeat kinase-2 (LRRK2) and α-synuclein (SNCA) loci are associated with Parkinson's disease (PD) risk. Viral infections have also been linked to increased risk of developing PD. In exploring a role for each of the encoded proteins in host response against brain-directed viral infections, we previously demonstrated that two Lrrk2 knock-in variants as well as Snca expression altered survival rates from viral encephalitis following intranasal inoculation of newborn mice with a double-stranded RNA virus: respiratory-enteric-orphan virus, serotype-3 strain Dearing (reovirus T3D). Here, we examined whether outcomes of direct inoculation of the brain by reovirus T3D, which invariably causes lethal encephalitis within 15 days, would also be modified by variants in Lrrk2 and Snca. When we inoculated newborn mice intracerebrally with reovirus T3D, we found that compared to wild-type littermates Lrrk2 p.G2019S kinase-hyperactive and p.D1994S kinase-inactive mutant mice did not show any significant difference in time-to-death or in viral titres in the brain, and revealed no sex difference. In parallel studies, the reduction or absence of endogenous α-synuclein did not alter the course of disease in reovirus T3D-infected mice. Together, these findings suggest that while variants in the PD-linked Lrrk2 and Snca genes influenced disease outcomes of intranasally acquired reovirus T3D encephalitis, they did not affect survival outcomes in the intracerebrally acquired reovirus T3D encephalitis model.
富含亮氨酸重复激酶2（LRRK2）和α-突触核蛋白（SNCA）基因座的变异与帕金森病（PD）风险相关。病毒感染也与患PD风险增加有关。在探索每种编码蛋白在宿主抵抗脑靶向病毒感染的反应中的作用时，我们之前证明，两种Lrrk2基因敲入变异以及Snca表达改变了新生小鼠经鼻接种双链RNA病毒（呼吸道肠道孤儿病毒3型迪林毒株，呼肠孤病毒T3D）后脑炎的存活率。在此，我们研究了呼肠孤病毒T3D直接脑内接种（该病毒在15天内总会导致致命性脑炎）的结果是否也会受到Lrrk2和Snca变异的影响。当我们给新生小鼠脑内接种呼肠孤病毒T3D时，我们发现，与野生型同窝小鼠相比，Lrrk2 p.G2019S激酶活性增强型和p.D1994S激酶失活型突变小鼠在死亡时间或脑内病毒滴度方面没有任何显著差异，且未显示出性别差异。在平行研究中，内源性α-突触核蛋白的减少或缺失并未改变呼肠孤病毒T3D感染小鼠的病程。总之，这些发现表明，虽然与PD相关的Lrrk2和Snca基因变异影响了经鼻感染呼肠孤病毒T3D脑炎的疾病结果，但它们并未影响脑内感染呼肠孤病毒T3D脑炎模型的存活结果。
