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首页 » 帕金森病 » 两项研究发现新的帕金森病生物标志物---磷酸化LRRK2蛋白

两项研究发现新的帕金森病生物标志物---磷酸化LRRK2蛋白

来源:生物谷 2016-07-08 08:32

2016年7月8日/生物谷BIOON/--在两项新的研究中,来自美国阿拉巴马大学的Andrew West博士和同事们通过分析帕金森病患者的尿液和脑脊髓液样品,发现尿液中的一种全新的生物标志物---磷酸化LRRK2蛋白---与帕金森病的存在和严重度相关联。他们正在更加深入地研究这些样品,以便验证是否能够利用这种生物标志物指导未来的临床治疗和在治疗期间实时地监控潜在新药物的疗效。

West说,“没有人想到我们能够在生物流体中测量到这种大分子蛋白的活性,这是因为它通常是在大脑中的神经元内发现的。”

相关研究结果首先发表在2016年3月15日那期Neurology期刊上,论文标题为“Urinary LRRK2 phosphorylation predicts parkinsonian phenotypes in G2019S LRRK2 carriers”,随后于2016年6月14日在线发表在Movement Disorders期刊上,论文标题为“Ser(P)-1292 LRRK2 in urinary exosomes is elevated in idiopathic Parkinson's disease”。

已证实这种生物标志物LRRK2在遗传性帕金森病中发挥着作用,最为常见的一种基因突变(G2019S)导致LRRK2激酶将太多的磷酸基团加到它自身和其他的蛋白上。这为何能够导致帕金森病到目前为止仍是不清楚的。

West的生物标志物鉴定方法的关键在于了解到LRRK2能够从所有人生物流体(如尿液和唾液)中发现的外泌体(exosome)内纯化出来。体内的细胞持续地释放含有蛋白、RNA和DNA混合物的外泌体。Wset和同事们能够从帕金森病患者捐献的3到4盎司尿液样品中纯化出外泌体,然后测量这些外泌体中的磷酸化LRRK2蛋白。

在发表在Neurology期刊上的研究中,West和同事们发现水平增加的磷酸化LRRK2蛋白能够预测携带LRRK2 G2019S基因突变的帕金森病患者的疾病发作风险。他们首先在14名携带LRRK2基因突变的帕金森病患者的尿液样品中进行测试,然后在72名携带LRRK2基因突变的帕金森病患者的尿液样品中进行重复测试。

在随后发表在Movement Disorders期刊上的研究中,West和同事们将研究范围扩大到没有携带LRRK2基因突变的人群,其中这些人大多数是帕金森病患者。利用来自帕金森病患者和健康对照者的158种尿液样品,West和同事们发现类似于携带LRRK2基因突变的帕金森病患者,大约20%没有携带LRRK2基因突变但患上帕金森病的患者也含有较高水平的磷酸化LRRK2蛋白,而这种情形并不存在于健康对照者体内。这项研究因此推断体内较高水平的磷酸化LRRK2蛋白可能是在未来开发出降低磷酸化LRRK2蛋白的药物的极好的候选生物标志物。(生物谷 Bioon.com)

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会议时间:2016.09.09-2016.09.10     会议地点:上海

会议详情: http://www.bioon.com/z/2016biomarker/>



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Urinary LRRK2 phosphorylation predicts parkinsonian phenotypes in G2019S LRRK2 carriers

Kyle B. Fraser, BS, Mark S. Moehle, BS, Roy N. Alcalay, MD, MS and Andrew B. West

doi:10.1212/WNL.0000000000002436
PMC:
PMID:

Objective: To test whether phosphorylated Ser-1292 LRRK2 levels in urine exosomes predicts LRRK2 mutation carriers (LRRK2+) and noncarriers (LRRK2?) with Parkinson disease (PD+) and without Parkinson disease (PD?).

Methods: LRRK2 protein was purified from urinary exosomes collected from participants in 2 independent cohorts. The first cohort included 14 men (LRRK2+/PD+, n = 7; LRRK2?/PD+, n = 4; LRRK2?/PD?, n = 3). The second cohort included 62 men (LRRK2?/PD?, n = 16; LRRK2+/PD?, n = 16; LRRK2+/PD+, n = 14; LRRK2?/PD+, n = 16). The ratio of Ser(P)-1292 LRRK2 to total LRRK2 was compared between LRRK2+/PD+ and LRRK2? in the first cohort and between LRRK2 G2019S carriers with and without PD in the second cohort.

Results: LRRK2+/PD+ had higher ratios of Ser(P)-1292 LRRK2 to total LRRK2 than LRRK2?/PD? (4.8-fold, p < 0.001) and LRRK2?/PD+ (4.6-fold, p < 0.001). Among mutation carriers, those with PD had higher Ser(P)-1292 LRRK2 to total LRRK2 than those without PD (2.2-fold, p < 0.001). Ser(P)-1292 LRRK2 levels predicted symptomatic from asymptomatic carriers with an area under the receiver operating characteristic curve of 0.844.

Conclusion: Elevated ratio of phosphorylated Ser-1292 LRRK2 to total LRRK2 in urine exosomes predicted LRRK2 mutation status and PD risk among LRRK2 mutation carriers. Future studies may explore whether interventions that reduce this ratio may also reduce PD risk.



Ser(P)-1292 LRRK2 in urinary exosomes is elevated in idiopathic Parkinson's disease

Kyle B. Fraser BS1, Ashlee B. Rawlins BS1, Rachel G. Clark BS1, Roy N. Alcalay MD, MS2, David G. Standaert MD, PhD1, Nianjun Liu PhD3, Parkinson's Disease Biomarker Program Consortium andAndrew B. West

doi:10.1002/mds.26686
PMC:
PMID:

Background
Mutations in Leucine-rich repeat kinase 2 (LRRK2) enhance levels of the autophosphorylated LRRK2 protein and are the most common known cause of inherited Parkinson's disease (PD). LRRK2 has been further implicated in susceptibility to idiopathic PD in genetic association studies.

Objective
The objective of this study was to compare autophosphorylated Ser(P)-1292 LRRK2 levels from biobanked urine samples with clinical data in PD patients and controls.

Methods
Ser(P)-1292 LRRK2 levels were measured from urine exosome fractions from 79 PD patients and 79 neurologically healthy controls enrolled in the Parkinson Disease Biomarker Program at the University of Alabama at Birmingham.

Results
Ser(P)-1292 LRRK2 levels were higher in men than women (P < .0001) and elevated in PD patients when compared with controls (P = .0014). Ser(P)-1292 LRRK2 levels were higher in PD cases with worse cognition and correlated with poor performance in MoCA (r = ?0.2679 [?0.4628 to ?0.0482]), MDS-UPDRS subscales 1 and 2 (r = 0.2239 [0.0014-0.4252], 0.3404 [0.1276-0.5233], respectively), Epworth Sleepiness Scale (r = 0.3215 [0.1066-0.5077]), and Modified Schwab and England Activities of Daily Living Scales (r = ?0.4455 [?0.6078 to ?0.2475]). Ser(P)-1292 LRRK2 levels predicted those with worse cognitive impairment in PD patients with some success (c = 0.73).

Conclusions
Urinary exosome Ser(P)-1292 LRRK2 levels are elevated in idiopathic PD and correlated with the severity of cognitive impairment and difficultly in accomplishing activities of daily living. These results implicate biochemical changes in LRRK2 in idiopathic PD.

 

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