Buck Silas A, Malankhanova Tuyana, Strader Samuel, Ma Eileen B, Yim Sarah, Pratt Harrison W, Ervin John, Lee Edward B, Wang Shih-Hsiu J, Cohen Todd J, West Andrew B, Sanders Laurie H
Department of Neurology, Duke University School of Medicine, Durham, NC, 27710, USA.
Department of Pathology, Duke University School of Medicine, Durham, NC, 27710, USA.
Acta Neuropathol. 2025 Oct 23;150(1):44. doi: 10.1007/s00401-025-02951-x.
Parkinson's disease (PD) pathogenic mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with endolysosomal dysfunction across cell types, and carriers of LRRK2 mutations variably present with phosphorylated tau and α-synuclein deposits in post-mortem analysis. LRRK2 mutations increase the phosphorylation of Rab substrates including Rab12 and Rab10. Rab12 and Rab10 are expressed in neuronal and non-neuronal cells with localization to membranes in the endolysosomal compartment, and lysosomal stress activates LRRK2 phosphorylation of Rabs. In this study, using antibodies directed to the LRRK2-mediated phosphorylation sites on Rab12 at amino acid Ser106 (pS106-Rab12) and Rab10 at amino acid Thr73 (pT73-Rab10), we test whether aberrant LRRK2 phosphorylation is associated with tau and/or α-synuclein pathology across clinically distinct neurodegenerative diseases. Analysis of brain tissue lysates and immunohistochemistry of pathology-susceptible brain regions demonstrate that pS106-Rab12 levels are increased in Alzheimer's disease (AD) and Lewy body disease (LBD), including PD with and without G2019S LRRK2 mutation. At early pathological stages, phosphorylated Rab12 localizes to granulovacuolar degeneration bodies (GVBs), which are thought to be active lysosomal-like structures, in neurons. pS106-Rab12-positive GVBs accumulate with pathological tau across brain tissues in AD and LBD, and in G2019S LRRK2 mutation carriers. In a mouse model of tauopathy, pS106-Rab12 localizes to GVBs during early tau deposition in an age-dependent manner. While GVBs are largely absent in neurons with mature protein pathology, subsets of both tau and α-synuclein inclusions appear to incorporate pS106-Rab12 at later pathological stages. Further, pS106-Rab12 labels GVBs in neurons and shows co-pathology with tau inclusions in primary tauopathies including Pick's disease, progressive supranuclear palsy, and corticobasal degeneration. Finally, pT73-Rab10 is elevated and localizes to GVBs, but not tau and α-synuclein inclusions, in AD and LBD, including G2019S LRRK2 mutation carriers. These results implicate LRRK2 kinase activity and Rab phosphorylation in endolysosomal dysfunction in tau- and α-synuclein-associated neurodegenerative diseases.
富含亮氨酸重复激酶2（LRRK2）中的帕金森病（PD）致病突变与多种细胞类型的内溶酶体功能障碍有关，并且在尸检分析中，LRRK2突变携带者的磷酸化tau和α-突触核蛋白沉积物表现各异。LRRK2突变会增加包括Rab12和Rab10在内的Rab底物的磷酸化。Rab12和Rab10在神经元和非神经元细胞中表达，定位于内溶酶体区室的膜上，并且溶酶体应激会激活Rab的LRRK2磷酸化。在本研究中，我们使用针对Rab12第106位氨基酸（pS106-Rab12）和Rab10第73位氨基酸（pT73-Rab10）上LRRK2介导的磷酸化位点的抗体，来测试异常的LRRK2磷酸化是否与临床上不同的神经退行性疾病中的tau和/或α-突触核蛋白病理学相关。对脑组织裂解物的分析以及对易出现病理学变化的脑区的免疫组织化学分析表明，在阿尔茨海默病（AD）和路易体病（LBD）中，包括携带和不携带G2019S LRRK2突变的PD患者，pS106-Rab12水平均升高。在早期病理阶段，磷酸化的Rab12定位于神经元中的颗粒空泡变性体（GVB），GVB被认为是活跃的溶酶体样结构。在AD和LBD以及G2019S LRRK2突变携带者的脑组织中，pS106-Rab12阳性的GVB与病理性tau一起积累。在tau病小鼠模型中，pS106-Rab12在tau早期沉积过程中以年龄依赖性方式定位于GVB。虽然在具有成熟蛋白质病理学的神经元中GVB基本不存在，但在后期病理阶段，tau和α-突触核蛋白包涵体的亚群似乎都掺入了pS106-Rab12。此外，pS106-Rab12标记神经元中的GVB，并在包括Pick病、进行性核上性麻痹和皮质基底节变性在内的原发性tau病中与tau包涵体表现出共同病理学特征。最后，在AD和LBD中，包括G2019S LRRK2突变携带者，pT73-Rab10升高并定位于GVB，但不定位于tau和α-突触核蛋白包涵体。这些结果表明LRRK2激酶活性和Rab磷酸化与tau和α-突触核蛋白相关的神经退行性疾病中的内溶酶体功能障碍有关。
