Abstract：
Mutations in the leucine rich repeat kinase 2 (LRRK2) gene are among the most common genetic causes of Lewy body Parkinson\'s disease (PD). However, LRRK2 mutations can also lead to a variety of pathological phenotypes other than typical PD, including relatively pure nigrostriatal cell loss without alpha-synuclein-positive Lewy bodies or Lewy neurites, progressive supranuclear palsy (PSP), and multiple system atrophy (MSA). The mechanisms behind this remarkable pleomorphic pathology are currently unclear.
To genetically and pathologically characterize a case with a LRRK2, p.Ile1371Val rare variant and pathologically proven MSA.
From the brain donation program at the Parkinson\'s Institute and Clinical Center, we selected 26 brains with family history and a with clinicopathological diagnosis of PD (n = 20), MSA (n = 4), or PSP (n = 2). We performed neuropathological evaluation, including alpha-synuclein and tau immunohistochemistry and sequenced 188 genes that have been reported as causative for or associated with neurodegenerative diseases.
We identified a known LRRK2, p.Ile1371Val genetic variant in a case with clinically diagnosed and pathologically proven MSA. Neuropathology revealed that the olivopontocerebellar system was more affected than the striatonigral system.
Our data suggest that genetic variants in the LRRK2 gene can present clinically and neuropathologically as MSA. One other LRRK2 genetic variant (LRRK2, p.Ile2020Thr) has been reported with a neuropathological diagnosis of MSA. Interestingly, the LRRK2 variant (LRRK2, p.Ile1371Val) identified here has been reported previously in a postmortem case with Lewy body PD.Future studies are critical to discover the mechanisms leading to different neurodegenerative trajectories both in neuronal and glial cell populations.
To genetically and pathologically characterize a case with a LRRK2, p.Ile1371Val rare variant and pathologically proven MSA.
From the brain donation program at the Parkinson\'s Institute and Clinical Center, we selected 26 brains with family history and a with clinicopathological diagnosis of PD (n = 20), MSA (n = 4), or PSP (n = 2). We performed neuropathological evaluation, including alpha-synuclein and tau immunohistochemistry and sequenced 188 genes that have been reported as causative for or associated with neurodegenerative diseases.
We identified a known LRRK2, p.Ile1371Val genetic variant in a case with clinically diagnosed and pathologically proven MSA. Neuropathology revealed that the olivopontocerebellar system was more affected than the striatonigral system.
Our data suggest that genetic variants in the LRRK2 gene can present clinically and neuropathologically as MSA. One other LRRK2 genetic variant (LRRK2, p.Ile2020Thr) has been reported with a neuropathological diagnosis of MSA. Interestingly, the LRRK2 variant (LRRK2, p.Ile1371Val) identified here has been reported previously in a postmortem case with Lewy body PD.Future studies are critical to discover the mechanisms leading to different neurodegenerative trajectories both in neuronal and glial cell populations.
摘要：
富含亮氨酸重复序列激酶2(LRRK2)基因的突变是路易体帕金森病(PD)最常见的遗传原因之一。然而,LRRK2突变还可导致除典型PD外的多种病理表型，包括相对纯的黑质纹状体细胞丢失，没有α-突触核蛋白阳性路易体或路易神经突，进行性核上性麻痹（PSP），多系统萎缩（MSA）。目前尚不清楚这种显着的多形性病理学背后的机制。
对患有LRRK2，p.Ile1371Val罕见变异并经病理证实的MSA的病例进行遗传和病理表征。
来自帕金森研究所和临床中心的大脑捐赠计划，我们选择了26个有家族史和临床病理诊断为PD的大脑(n=20)，MSA（n=4），或PSP(n=2)。我们进行了神经病理学评估，包括α-突触核蛋白和tau免疫组织化学，并测序了188个被报道为神经退行性疾病的病因或与之相关的基因。
我们在临床诊断和病理证实的MSA病例中鉴定了已知的LRRK2，p.Ile1371Val遗传变异。神经病理学显示，橄榄脑桥小脑系统比纹状体系统受到的影响更大。
我们的数据表明，LRRK2基因中的遗传变异体可在临床和神经病理学上表现为MSA。已经报道了另一种LRRK2遗传变异(LRRK2,p.Ile2020Thr)与MSA的神经病理学诊断。有趣的是,LRRK2变异体(LRRK2,p.Ile1371Val)先前已在路易体PD的死后病例中报道。未来的研究对于发现导致神经元和神经胶质细胞群体中不同神经变性轨迹的机制至关重要。
对患有LRRK2，p.Ile1371Val罕见变异并经病理证实的MSA的病例进行遗传和病理表征。
来自帕金森研究所和临床中心的大脑捐赠计划，我们选择了26个有家族史和临床病理诊断为PD的大脑(n=20)，MSA（n=4），或PSP(n=2)。我们进行了神经病理学评估，包括α-突触核蛋白和tau免疫组织化学，并测序了188个被报道为神经退行性疾病的病因或与之相关的基因。
我们在临床诊断和病理证实的MSA病例中鉴定了已知的LRRK2，p.Ile1371Val遗传变异。神经病理学显示，橄榄脑桥小脑系统比纹状体系统受到的影响更大。
我们的数据表明，LRRK2基因中的遗传变异体可在临床和神经病理学上表现为MSA。已经报道了另一种LRRK2遗传变异(LRRK2,p.Ile2020Thr)与MSA的神经病理学诊断。有趣的是,LRRK2变异体(LRRK2,p.Ile1371Val)先前已在路易体PD的死后病例中报道。未来的研究对于发现导致神经元和神经胶质细胞群体中不同神经变性轨迹的机制至关重要。
