PATHOLOGIC LRRK2 SIGNALING IN FAMILIAL AND IDIOPATHIC PARKINSON'S DISEASE

家族性和特发性帕金森病中的病理性 LRRK2 信号传导

• 批准号: 10459599
• 负责人: Matthew J Lavoie
• 金额: $ 35.12万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10459599
• 关键词: Address; Adult; Affect; Age; American; Attention; Autopsy; Binding; Biochemical; Biochemistry; Biological Assay; Biological Markers; Biology; Brain; Cell Line; Cells; Cellular biology; Clinical Research; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Data; Defect; Deposition; Dimerization; Disease; Engineering; Exhibits; Family; Functional disorder; Generations; Genes; Genetic; Goals; Guanosine Triphosphate Phosphohydrolases; Health; Human; Idiopathic Parkinson Disease; Impairment; In Vitro; Induced pluripotent stem cell derived neurons; Institutes; Intracellular Transport; Knock-in Mouse; LRRK2 gene; Lewy Bodies; Lewy body pathology; Lewy neurites; Link; Lysosomes; Mediating; Membrane; Metabolism; Monomeric GTP-Binding Proteins; Morphology; Mus; Mutation; Nature; Neurodegenerative Disorders; Neuroglia; Neuronal Dysfunction; Neurons; Organelles; Outcome; PINK1 gene; Parkinson Disease; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Patients; Penetrance; Peripheral; Phenotype; Phosphorylation; Phosphotransferases; Physiological; Play; Pre-Clinical Model; Process; Protein Sortings; Proteins; Regulation; Reporting; Role; Seeds; Series; Signal Pathway; Signal Transduction; Structure of parenchyma of lung; Study models; System; The Sun; Time; Tissues; Translating; alpha synuclein; autosomal dominant mutation; brain tissue; experimental study; human disease; insight; kinase inhibitor; link protein; mutant; neuropathology; novel; protein biomarkers; rab GTP-Binding Proteins; synuclein; synucleinopathy; tissue resource; trafficking

Parkinson’s disease (PD) is the second most common neurodegenerative disorder. While the causes of PD are not fully known, the rare familial forms of the disease continue to provide valuable insight into pathways that contribute to disease. For example, alpha-synuclein was discovered to be the major protein component of Lewy bodies only after the gene encoding it was linked to familial PD. Autosomal dominant mutations in LRRK2 are the most frequent genetic cause of PD, with patients most commonly presenting with late onset and classic Lewy body/synuclein pathology. We recently reported that endogenous expression of G2019S LRRK2, the most frequent pathogenic mutation, induces lysosomal abnormalities and the accumulation of insoluble synuclein in neurons. Notably, these effects were reversed by LRRK2 kinase inhibitors. However, the LRRK2 substrates that are aberrantly phosphorylated by G2019S LRRK2 to produce these defects, and whether these changes represent a final common pathologic pathway for all LRRK2 mutations and idiopathic PD, is not known. A subset of the Rab family of small GTPases are now recognized as physiological substrates of LRRK2 kinase activity. Rabs are critically involved in intracellular trafficking and exert powerful influence on the function of many organelles, including lysosomes. We have focused our attention here on Rab8a as a critical intermediary in PD pathogenesis. Rab8a is not only a substrate of LRRK2, but has been linked to other familial and idiopathic forms of PD. While all PD mutations appear to increase Rab phosphorylation, the R1441C mutation in LRRK2 possesses far greater Rab-kinase activity than G2019S. This could translate to greater neuronal dysfunction but has not be adequately addressed. Given the PD-relevant outcomes we recently established for G2019S LRRK2, we will determine here whether the R1441C mutation exerts greater defects in lysosome function and synuclein metabolism using both mouse primary neurons and human iPSC-derived neurons. We will then examine the relative effects of G2019S and R1441C LRRK2 on Rab8a biochemistry and biology, and dissect the precise role of Rab8a in LRRK2-mediated neuronal pathology. Lastly, we will investigate whether dysregulation of LRRK2 signaling pathways contribute to idiopathic PD. Through a careful analysis of post mortem brain tissue from idiopathic PD patients and age-matched controls, we will interrogate the status of multiple upstream and downstream features of LRRK2 protein and markers of LRRK2 kinase activity. We have assembled a team with deep expertise in cell biology and neuropathology and will complete a series of critical and timely experiments to provide much-needed insight into the mechanistic and pathogenic consequences of disease-linked LRRK2 mutations in neurons, and whether these pathways are involved in the far more common idiopathic cases of PD.

帕金森病（PD）是第二常见的神经退行性疾病。虽然原因 PD还不完全清楚，罕见的家族性疾病继续提供有价值的洞察途径 导致疾病。例如，α-突触核蛋白被发现是神经胶质瘤的主要蛋白质组分。 路易体只有在编码它的基因与家族性PD相关后才出现。 LRRK 2的常染色体显性突变是PD最常见的遗传原因，患者 最常见的表现为迟发性和典型的路易体/突触核蛋白病理。我们最近报道 G2019 S LRRK 2的内源性表达，最常见的致病性突变，诱导溶酶体 异常和不溶性突触核蛋白在神经元中的积累。值得注意的是， LRRK 2激酶抑制剂。然而，被G2019 S异常磷酸化的LRRK 2底物， LRRK 2产生这些缺陷，以及这些变化是否代表最终的共同病理途径 对于所有LRRK 2突变和特发性PD，尚不清楚。 Rab家族的小GTP酶的一个子集现在被认为是LRRK 2的生理底物 激酶活性Rabs主要参与细胞内运输，并对细胞内转运产生强大的影响。 许多细胞器的功能，包括溶酶体。我们把注意力集中在Rab 8a上， 在PD发病机制中起重要作用。Rab 8a不仅是LRRK 2的底物，而且与其他家族性疾病有关。 和特发性PD。虽然所有的PD突变似乎都增加了Rab磷酸化，但R1441 C突变增加了Rab磷酸化。 LRRK 2中的突变具有比G2019 S大得多的Rab-kinase活性。这可以转化为更大的 神经元功能障碍，但尚未得到充分解决。鉴于PD相关的结果，我们最近 对于G2019 S LRRK 2，我们将在这里确定R1441 C突变是否在G2019 S LRRK 2中产生更大的缺陷。 使用小鼠原代神经元和人iPSC衍生的溶酶体功能和突触核蛋白代谢 神经元然后，我们将检查G2019 S和R1441 C LRRK 2对Rab 8a生物化学的相对影响， 生物学，并剖析Rab 8a在LRRK 2介导的神经元病理学中的确切作用。最后，我们将 研究LRRK 2信号通路的失调是否有助于特发性PD。通过认真 分析特发性PD患者和年龄匹配对照的死后脑组织，我们将询问 LRRK 2蛋白多个上下游特征及其标志物研究现状 活动我们已经组建了一支在细胞生物学和神经病理学方面具有深厚专业知识的团队，并将完成一项 一系列关键和及时的实验，以提供急需的洞察机制和致病性 神经元中与疾病相关的LRRK 2突变的后果，以及这些途径是否参与了神经元的疾病相关性。 更常见的特发性帕金森病

项目成果

The LRRK2 kinase substrates Rab8a and Rab10 contribute complementary but distinct disease-relevant phenotypes in human neurons.

LRRK2 激酶底物 Rab8a 和 Rab10 在人类神经元中贡献互补但不同的疾病相关表型。

• DOI: 10.1101/2023.04.30.538317
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Mamais,Adamantios;Sanyal,Anwesha;Fajfer,Austin;Zykoski,CatherineG;Guldin,Michael;Riley-DiPaolo,Alexis;Subrahmanian,Nitya;Gibbs,Whitney;Lin,Steven;LaVoie,MatthewJ
• 通讯作者: LaVoie,MatthewJ

Mutations in LRRK2 linked to Parkinson disease sequester Rab8a to damaged lysosomes and regulate transferrin-mediated iron uptake in microglia.

• DOI: 10.1371/journal.pbio.3001480
• 发表时间: 2021-12
• 期刊: PLoS biology
• 影响因子: 9.8
• 作者: Mamais A;Kluss JH;Bonet-Ponce L;Landeck N;Langston RG;Smith N;Beilina A;Kaganovich A;Ghosh MC;Pellegrini L;Kumaran R;Papazoglou I;Heaton GR;Bandopadhyay R;Maio N;Kim C;LaVoie MJ;Gershlick DC;Cookson MR
• 通讯作者: Cookson MR

LRRK2 Kinase Inhibition Rescues Deficits in Lysosome Function Due to Heterozygous GBA1 Expression in Human iPSC-Derived Neurons.

LRRK2 激酶抑制可挽救人 iPSC 衍生神经元中因杂合 GBA1 表达而导致的溶酶体功能缺陷。

• DOI: 10.3389/fnins.2020.00442
• 发表时间: 2020
• 期刊: Frontiers in neuroscience
• 影响因子: 4.3
• 作者: Sanyal,Anwesha;Novis,HaileyS;Gasser,Emile;Lin,Steven;LaVoie,MatthewJ
• 通讯作者: LaVoie,MatthewJ