Gustavsson Emil K, Follett Jordan, Trinh Joanne, Barodia Sandeep K, Real Raquel, Liu Zhiyong, Grant-Peters Melissa, Fox Jesse D, Appel-Cresswell Silke, Stoessl A Jon, Rajput Alex, Rajput Ali H, Auer Roland, Tilney Russel, Sturm Marc, Haack Tobias B, Lesage Suzanne, Tesson Christelle, Brice Alexis, Vilariño-Güell Carles, Ryten Mina, Goldberg Matthew S, West Andrew B, Hu Michele T, Morris Huw R, Sharma Manu, Gan-Or Ziv, Samanci Bedia, Lis Pawel, Tocino Teresa, Amouri Rim, Sassi Samia Ben, Hentati Faycel, Tonelli Francesca, Alessi Dario R, Farrer Matthew J
Department of Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.
Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
medRxiv. 2024 Jan 18:2024.01.17.24300927. doi: 10.1101/2024.01.17.24300927.
Parkinson's disease (PD) is a progressive neurodegenerative disorder. Mendelian forms have revealed multiple genes, with a notable emphasis on membrane trafficking; RAB GTPases play an important role in PD as a subset are both regulators and substrates of LRRK2 protein kinase. To explore the role of RAB GTPases in PD, we undertook a comprehensive examination of their genetic variability in familial PD.
Affected probands from 130 multi-incident PD families underwent whole-exome sequencing and genotyping, Potential pathogenic variants in 61 RAB GTPases were genotyped in relatives to assess disease segregation. These variants were also genotyped in a larger case-control series, totaling 3,078 individuals (2,734 with PD). The single most significant finding was subsequently validated within genetic data (6,043 with PD). Clinical and pathologic findings were summarized for gene-identified patients, and haplotypes were constructed. In parallel, wild-type and mutant RAB GTPase structural variation, protein interactions, and resultant enzyme activities were assessed.
We found c.213C>G (Ser71Arg) to co-segregate with autosomal dominant parkinsonism in three multi-incident families. Ser71Arg was also significantly associated with PD in case-control samples: genotyping and database searches identified thirteen more patients with the same variant that was absent in unaffected controls. Notably, Ser71Arg heterozygotes share a common haplotype. At autopsy, one patient had sparse neurofibrillary tangle pathology in the midbrain and thalamus, without Lewy body pathology. In transfected cells the RAB32 Arg71 was twice as potent as Ser71 wild type to activate LRRK2 kinase.
Our study provides unequivocal evidence to implicate RAB32 Ser71Arg in PD. Functional analysis demonstrates LRRK2 kinase activation. We provide a mechanistic explanation to expand and unify the etiopathogenesis of monogenic PD.
National Institutes of Health, the Canada Excellence Research Chairs program, Aligning Science Across Parkinson's, the Michael J. Fox Foundation for Parkinson's Research, and the UK Medical Research Council.
帕金森病（PD）是一种进行性神经退行性疾病。孟德尔形式的帕金森病已揭示出多个相关基因，尤其着重于膜运输；RAB GTP酶在帕金森病中发挥重要作用，因为其中一部分既是富含亮氨酸重复激酶2（LRRK2）蛋白激酶的调节因子，也是其底物。为了探究RAB GTP酶在帕金森病中的作用，我们对家族性帕金森病中它们的基因变异性进行了全面检测。
来自130个多发病例帕金森病家族的患病先证者接受了全外显子组测序和基因分型，对61种RAB GTP酶中的潜在致病变异在亲属中进行基因分型以评估疾病的遗传分离情况。这些变异还在一个更大的病例对照系列中进行了基因分型，该系列共有3078名个体（2734名帕金森病患者）。随后在遗传数据（6043名帕金森病患者）中对最显著的单一发现进行了验证。对基因鉴定出的患者的临床和病理结果进行了总结，并构建了单倍型。同时，评估了野生型和突变型RAB GTP酶的结构变异、蛋白质相互作用以及由此产生的酶活性。
我们发现c.213C>G（Ser71Arg）在三个多发病例家族中与常染色体显性帕金森综合征共分离。在病例对照样本中，Ser71Arg也与帕金森病显著相关：基因分型和数据库搜索又发现了13名具有相同变异的患者，而未受影响的对照中不存在该变异。值得注意的是，Ser71Arg杂合子共享一个常见单倍型。尸检时，一名患者中脑和丘脑有稀疏的神经原纤维缠结病理改变，但无路易小体病理改变。在转染细胞中，RAB32 Arg71激活LRRK2激酶的能力是Ser71野生型的两倍。
我们的研究提供了明确证据表明RAB32 Ser71Arg与帕金森病有关。功能分析显示了LRRK2激酶的激活。我们提供了一种机制性解释，以扩展和统一单基因帕金森病的病因发病机制。
美国国立卫生研究院、加拿大卓越研究主席计划、帕金森病科学整合项目、迈克尔·J·福克斯帕金森病研究基金会以及英国医学研究理事会。
