LRRK2 modifies α-syn pathology and spread in mouse models and human neurons
LRRK2 modifies α-syn pathology and spread in mouse models and human neurons
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DOI：
10.1007/s00401-019-01995-0
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发表时间：
2019-06-01
影响因子：
12.7
通讯作者：
Gitler, Aaron D.
中科院分区：
文献类型：
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作者：
Bieri, Gregor;Brahic, Michel;Gitler, Aaron D.
蛋白质α-突触核蛋白（α-syn）的进行性聚集和黑质丘脑部（SNpc）中多巴胺能神经元的损失是帕金森病（PD）的关键组织病理学标志。越来越多的证据表明，α-syn病理学可以通过大脑中的神经元回路传播，从而导致疾病的进行性。因此，将α-syn传递和聚集的修饰剂鉴定为减缓疾病进展的潜在靶标在治疗上是相关的。在家族性和散发性PD的研究中，已经确定了越来越多的基因突变和风险因素。然而，这些基因如何影响alpha-syn聚集和病理传播，以及它们是否可以作为治疗干预的靶点，仍然不清楚。我们进行了有针对性的遗传筛选的风险基因与PD和帕金森症的修饰剂的α-syn聚集，使用α-syn预形成的原纤维（PFF）诱导试验。我们发现，Lrrk 2和Gba的表达减少调节小鼠原代神经元中的α-syn聚集。相反，在表达PD连锁LRRK 2 G2019 S突变的小鼠的原代神经元中，α-syn聚集增加。在体内，使用LRRK 2 G2019 S转基因小鼠，我们观察到α-syn聚集的加速和SNpc中多巴胺能神经元的变性，加剧了变性相关的神经炎症和行为缺陷。为了在人类背景下验证我们的发现，我们使用诱导多能干细胞（iPS）衍生的神经元（iN）建立了一种新的人类α-syn传递模型，其中人类α-syn PFF以时间依赖性方式触发内源性α-syn的聚集。在PD受试者来源的iN中，G2019 S突变增强了α-syn聚集，而LRRK 2的缺失降低了聚集。总的来说，这些发现在小鼠和人类模型中建立了PD风险基因LRRK 2和α-syn传播之间的强相互作用。由于LRRK 2抑制剂在PD中的临床试验目前正在进行中，我们的研究结果提出了这些抑制剂在PD中广泛有效的可能性，超出了LRRK 2突变引起的病例。
Progressive aggregation of the protein alpha-synuclein (alpha-syn) and loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) are key histopathological hallmarks of Parkinson's disease (PD). Accruing evidence suggests that alpha-syn pathology can propagate through neuronal circuits in the brain, contributing to the progressive nature of the disease. Thus, it is therapeutically pertinent to identify modifiers of alpha-syn transmission and aggregation as potential targets to slow down disease progression. A growing number of genetic mutations and risk factors has been identified in studies of familial and sporadic forms of PD. However, how these genes affect alpha-syn aggregation and pathological transmission, and whether they can be targeted for therapeutic interventions, remains unclear. We performed a targeted genetic screen of risk genes associated with PD and parkinsonism for modifiers of alpha-syn aggregation, using an alpha-syn preformed-fibril (PFF) induction assay. We found that decreased expression of Lrrk2 and Gba modulated alpha-syn aggregation in mouse primary neurons. Conversely, alpha-syn aggregation increased in primary neurons from mice expressing the PD-linked LRRK2 G2019S mutation. In vivo, using LRRK2 G2019S transgenic mice, we observed acceleration of alpha-syn aggregation and degeneration of dopaminergic neurons in the SNpc, exacerbated degeneration-associated neuroinflammation and behavioral deficits. To validate our findings in a human context, we established a novel human alpha-syn transmission model using induced pluripotent stem cell (iPS)-derived neurons (iNs), where human alpha-syn PFFs triggered aggregation of endogenous alpha-syn in a time-dependent manner. In PD subject-derived iNs, the G2019S mutation enhanced alpha-syn aggregation, whereas loss of LRRK2 decreased aggregation. Collectively, these findings establish a strong interaction between the PD risk gene LRRK2 and alpha-syn transmission across mouse and human models. Since clinical trials of LRRK2 inhibitors in PD are currently underway, our findings raise the possibility that these may be effective in PD broadly, beyond cases caused by LRRK2 mutations.