Phenotypic Spectrum of LRRK2 Mutations

描述(由申请者提供)：制定策略以确定帕金森病(PD)的风险个体，并采取干预措施防止其发病，可能是减轻疾病负担的最大希望。由于帕金森病的发病率相对较低，难以确定表型转化的高风险样本，以及缺乏预防性治疗的分子靶标，预防性研究一直受到限制。富亮氨酸重复蛋白激酶(LRRK2)基因突变是帕金森病(PD)最常见的单基因致病因素，这一发现为解决这些挑战提供了机会。在德系犹太人中，G2019S突变占帕金森病的20%，而LRRK2被认为是一个可用药的靶点，使LRRK2帕金森病本身就是一种重要的疾病。LRRK2 PD在临床特征、生物标志物、病理和治疗反应方面也与特发性PD(IPD)相似，使其总体上成为一个很有前途的模型。为了兑现这一承诺，我们必须首先更好地表征突变携带者的表型表达范围。对表型异质性的更多了解包括非运动性和早期运动性特征。非运动性异常，如嗅觉障碍、黑质高回声和自主神经功能障碍，可在明显的运动体征和临床诊断帕金森病之前发生。这些特征，以及非皮肤癌，已经在LRRK2PD中被报道，然而，它们的患病率和对表现为PD的预测有效性尚不清楚。对大量LRRK2突变PD受试者和无PD携带者的评估将有助于确定非运动性异常和非皮肤癌是否是独立于PD(风险标记物)的发展的突变效应，或者表现在可能处于运动恶化轨迹或已诊断为PD(进展标记物)的个体中。此外，量化非运动性和早期运动性PD的存在和特征将有助于阐明人类LRRK2的病理生理学，并有助于建立疾病负担领域。这一建议为确定LRRK2 G2019在未显性携带者(NMC)以及已确诊的LRKK2 PD(MC)患者中的表型迈出了重要的一步，并将有助于为LRRK2 NMC的纵向研究铺平道路。这项研究建立在My K23期间进行的研究基础上，并利用了由福克斯基金会资助的两项当前研究，即关于德系犹太人帕金森病的联合会研究(联合会，贝丝以色列，哥伦比亚，特拉维夫)，以及对LRRK2 PD联合会受试者的一级亲属子集的DaTSCAN研究(神经退行性疾病研究所，IND研究)。它将关键地扩展这两项研究，在纽约和以色列站点(AIM 1)增加措施，包括癌症评估(AIM 3)，并将联合会标记数据与多巴胺能功能障碍的替代标记(AIM 2)相结合。这项研究，加上遗传学、流行病学和经颅超声的结构化培训计划，将帮助我发展成为一名帕金森病(PD)研究人员，通过更好地描述疾病特征和了解帕金森症的标志，促进帕金森疗法的开发、测试和早期应用。我在运动障碍和流行病学方面有广泛的培训，并发表了关于LRRK2 PD、Gaucher相关性PD和与PD相关的生物标记物的文章，特别是螺旋分析和经颅超声检查。K02中拟议的教育计划将使我能够通过课程学习、实践培训和研究性学习，加深我在遗传学、表观遗传学和经颅超声成像领域的知识和专业知识，以及流行病学领域的知识和专业知识。如上所述，这项研究将通过增加措施和新的分析，在一项大型联合会研究的基础上，扩大对有帕金森氏综合症、家庭成员和对照的一群独特的德系犹太人的研究。目的1比较不同亚组突变携带者、无LRRK2 G2019S突变的帕金森病患者和对照组之间的非运动性、定量运动和影像指标。在目标3中，将测试非皮肤癌和LRRK2 PD之间的关联。最后，在目标2中，DAT扫描将被用作PD发展的替代结局标志，因为进展不能直接在横断面上研究。作为本研究的直接结果，对计划中的R01中非运动特征的进展进行纵向分析将允许确定A)预测表型转换的标记的算法，以及B)标记进展相对于帕金森病发作的斜率，以及确定在表现为帕金森病之前存在的中间状态。

DESCRIPTION (provided by applicant): Developing strategies to identify individuals at risk for Parkinson disease (PD) and interventions to prevent its onset may be the best hope for reducing the disease burden. Preventative research has been limited by the relatively low incidence of PD, difficulties in defining samples at high risk for phenoconversion, and the lack of molecular targets for preventive treatments. The discovery that mutations in the leucine rich repeat kinase kinase (LRRK2) gene comprise the most common monogenic etiology of Parkinson disease (PD) provides an opportunity to address many of these challenges. The G2019S mutation accounts for up to 20% of PD in Ashkenazi Jews, and LRRK2 is considered a druggable target, making LRRK2 PD an important disease in its own right. LRRK2 PD also resembles idiopathic PD (IPD) in terms of clinical features, biomarkers, pathology and response to treatment, making it overall a model of great promise. To deliver on this promise, we must first better characterize the range of phenotypic expression in mutation carriers. Greater understanding of the phenotypic heterogeneity includes non-motor and early motor features. Non-motor abnormalities such as olfactory dysfunction, hyperechogenicity of the substantia nigra, and dysautonomia may occur before overt motor signs and clinical diagnosis of PD. These features, as well as non-skin cancer, have been reported in LRRK2 PD, however, their prevalence and predictive validity for manifesting PD is not known. Evaluation of a larger number of LRRK2 mutation PD subjects and carriers without PD will help determine whether non-motor abnormalities and non-skin cancer are mutation effects independent of development of PD (risk markers), or manifest in individuals who may be on the trajectory to motor worsening or have diagnosed PD (progression markers). Further, quantifying the presence and characteristics of non-motor and early motor PD features will illuminate human LRRK2 pathophysiology and help establish domains of disease burden. This proposal takes important steps towards defining the phenotype of LRRK2 G2019 in nonmanifesting carriers (NMC), as well as and in persons with established LRKK2 PD (MC), and will help pave the way for longitudinal study of LRRK2 NMC. This research builds on studies conducted during my K23 and capitalizes on two current studies funded by the Fox Foundation, the Consortium study of PD in Ashkenazi Jews (the Consortium, Beth Israel, Columbia, Tel Aviv), and a DaTSCAN study in a subset of first degree relatives of LRRK2 PD Consortium subjects (the Institute for Neurodegenerative Disease, IND study). It will critically expand both studies by adding measures to both New York and Israeli sites (Aim 1), including cancer assessment (Aim 3), and combining Consortium marker data with a surrogate marker for dopaminergic dysfunction (Aim 2). This research, together with a program of structured training in genetics, epidemiology and transcranial sonography will help me develop as a Parkinson disease (PD) researcher who will facilitate the development, testing and early application of Parkinson therapeutics through better characterization of the disease, and understanding markers of parkinsonism. I have extensive training in movement disorders and epidemiology, and have published on LRRK2 PD, Gaucher associated PD, and biomarkers associated with PD, particularly spiral analysis and transcranial sonography. The proposed educational plan in the K02 would allow me to deepen my knowledge and expertise in the areas of genetics, epigenetics, and imaging with transcranial sonography, and epidemiology through coursework, practical training and the research study. As noted, this study will expand on a large Consortium study of a unique cohort of Ashkenazi Jews with PD, family members and controls, by adding measures and new analyses. In Aim 1 candidate non-motor, quantitative motor and imaging measures will be compared between different subgroups of mutation carriers, PD without LRRK2 G2019S mutation, and controls. In Aim 3, the association between non-skin cancer and LRRK2 PD will be tested. Finally in Aim 2, DAT scan will be used as a surrogate outcome marker for development of PD, as progression cannot be directly studied in cross-section. Longitudinal analysis of progression of non-motor features in the planned R01 as a direct outgrowth of this study will allow determination of A) an algorithm of markers which predicts phenoconversion, and B) the slopes of marker progression relative to the onset of PD, and the determination of an intermediary state which is present prior to manifesting PD.