Leucine-rich Repeat Kinase 2 (LRRK2) Pharmacological Inhibition Abates α-Synuclein Gene-induced Neurodegeneration
Leucine-rich Repeat Kinase 2 (LRRK2) Pharmacological Inhibition Abates α-Synuclein Gene-induced Neurodegeneration
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DOI：
10.1074/jbc.m115.660001
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发表时间：
2015-08-07
影响因子：
4.8
通讯作者：
West, Andrew B.
中科院分区：
文献类型：
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作者：
Daher, Joao P. L.;Abdelmotilib, Hisham A.;West, Andrew B.
目前尚不存在减缓或阻断帕金森病（PD）进展的治疗方法。遗传和生化研究表明α -突触核蛋白和富含亮氨酸的重复激酶2 （LRRK2）与迟发性帕金森病有关。LRRK2激酶活性与神经退行性通路有关。然而，LRRK2激酶抑制剂的治疗潜力尚不清楚，因为一类LRRK2激酶抑制剂具有显著的毒性。此外，LRRK2激酶抑制剂尚未在α -突触核蛋白诱导的神经变性模型中进行有效性测试。为了更好地了解LRRK2激酶抑制在PD中的治疗潜力，我们评估了LRRK2激酶抑制剂PF-06447475在预防α -突触核蛋白诱导的大鼠神经变性方面的耐受性和有效性。将野生型大鼠和转基因G2019S-LRRK2大鼠颅内注射在黑质中表达人α -突触核蛋白的腺相关病毒载体。大鼠在病毒转导后用PF-06447475或对照化合物治疗4周。我们发现，表达G2019S-LRRK2的大鼠对α -突触核蛋白的过度表达做出反应，加重了多巴胺能神经变性和炎症。LRRK2激酶抑制可以减轻与G2019S-LRRK2表达相关的神经变性和神经炎症。此外，PF-06447475对野生型大鼠具有神经保护作用。我们未发现PF-06447475治疗大鼠的肺、肾或肝脏的不良病理指征。这些结果表明，LRRK2的药理抑制在大鼠4周的时间内具有良好的耐受性，并且可以抵消急性α -突触核蛋白过度表达引起的多巴胺能神经变性。
Therapeutic approaches to slow or block the progression of Parkinson disease (PD) do not exist. Genetic and biochemical studies implicate alpha-synuclein and leucine-rich repeat kinase 2 (LRRK2) in late-onset PD. LRRK2 kinase activity has been linked to neurodegenerative pathways. However, the therapeutic potential of LRRK2 kinase inhibitors is not clear because significant toxicities have been associated with one class of LRRK2 kinase inhibitors. Furthermore, LRRK2 kinase inhibitors have not been tested previously for efficacy in models of alpha-synuclein-induced neurodegeneration. To better understand the therapeutic potential of LRRK2 kinase inhibition in PD, we evaluated the tolerability and efficacy of a LRRK2 kinase inhibitor, PF-06447475, in preventing alpha-synuclein-induced neurodegeneration in rats. Both wild-type rats as well as transgenic G2019S-LRRK2 rats were injected intracranially with adeno-associated viral vectors expressing human alpha-synuclein in the substantia nigra. Rats were treated with PF-06447475 or a control compound for 4 weeks post-viral transduction. We found that rats expressing G2019S-LRRK2 have exacerbated dopaminergic neurodegeneration and inflammation in response to the overexpression of alpha-synuclein. Both neurodegeneration and neuro-inflammation associated with G2019S-LRRK2 expression were mitigated by LRRK2 kinase inhibition. Furthermore, PF-06447475 provided neuroprotection in wild-type rats. We could not detect adverse pathological indications in the lung, kidney, or liver of rats treated with PF-06447475. These results demonstrate that pharmacological inhibition of LRRK2 is well tolerated for a 4-week period of time in rats and can counteract dopaminergic neurodegeneration caused by acute alpha-synuclein overexpression.