Dues Dylan J, Moore Darren J
Center for Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, United States.
Front Neurosci. 2020 Jul 8;14:719. doi: 10.3389/fnins.2020.00719. eCollection 2020.
Mutations in () instigate an autosomal dominant form of Parkinson's disease (PD). Despite the neuropathological heterogeneity observed in -PD, accumulating evidence suggests that alpha-synuclein and tau pathology are observed in a vast majority of cases. Intriguingly, the presence of protein aggregates spans both -PD and idiopathic disease, supportive of a common pathologic mechanism. Thus, it is important to consider how LRRK2 mutations give rise to such pathology, and whether targeting LRRK2 might modify the accumulation, transmission, or toxicity of protein aggregates. Likewise, it is not clear how LRRK2 mutations drive PD pathogenesis, and whether protein aggregates are implicated in LRRK2-dependent neurodegeneration. While animal models have been instrumental in furthering our understanding of a potential interaction between LRRK2 and protein aggregation, the biology is far from clear. We aim to provide a thoughtful overview of the evidence linking LRRK2 to protein aggregation in animal models.
亮氨酸重复激酶2（LRRK2）突变引发帕金森病（PD）的常染色体显性遗传形式。尽管在LRRK2相关帕金森病中观察到神经病理学异质性，但越来越多的证据表明，绝大多数病例中都存在α-突触核蛋白和tau病理改变。有趣的是，蛋白聚集体在LRRK2相关帕金森病和特发性疾病中均有出现，这支持了一种共同的病理机制。因此，了解LRRK2突变如何导致这种病理改变，以及靶向LRRK2是否可能改变蛋白聚集体的积累、传播或毒性非常重要。同样，目前尚不清楚LRRK2突变如何驱动帕金森病的发病机制，以及蛋白聚集体是否与LRRK2相关的神经退行性变有关。虽然动物模型有助于我们进一步了解LRRK2与蛋白聚集之间的潜在相互作用，但其中的生物学机制仍远未明确。我们旨在对动物模型中LRRK2与蛋白聚集之间的证据进行深入综述。
