Al-Lahham Rabab, Corkins Mark E, Ishtikhar Mohd, Rabadia Prakruti, Ramirez Santiago, Banerjee Victor, Shahnawaz Mohammad
Mitchell Center for Alzheimer's Disease and Related Brain Disorders, Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Cells. 2025 May 9;14(10):684. doi: 10.3390/cells14100684.
Lewy Body Disease (LBD) and Multiple System Atrophy (MSA) are synucleinopathies with distinct prognoses and neuropathologies, however, with overlapping clinical symptoms. Different disease characteristics are proposed to be determined by distinct conformations of alpha-synuclein (α-Syn) aggregates, which can self-propagate and spread between cells via a prion-like mechanism. The goal of this study is to investigate whether α-syn aggregates amplified from brain and CSF samples of LBD and MSA patients using the Seed Amplification Assay (SAA) maintain α-Syn seeding properties similar to those of α-syn aggregates derived from patients' brains. To address this, SAA-amplified and un-amplified α-Syn aggregates from LBD and MSA patients' brains, as well as SAA-amplified α-Syn aggregates from LBD and MSA patients' CSF samples, were used to treat synuclein biosensor cells, and induced intracellular α-Syn inclusions were analyzed by confocal microscopy. Our data indicate that induced α-Syn aggregates from LBD and MSA patients' brains have similar seeding properties and morphological characteristics in the α-Syn biosensor cells as those amplified from LBD and MSA patients' brains, as well as those amplified from LBD and MSA patients' CSF samples. In this study, we demonstrated that, regardless of the source of aggregates, the seeds from LBD and MSA produce cellular accumulation of α-Syn with distinct morphologies, confirming the presence of different conformational strains of α-Syn in LBD and MSA and allowing us to differentiate synucleinopathies based on the morphology of aggregates and seeding properties.
路易体病（LBD）和多系统萎缩（MSA）是具有不同预后和神经病理学特征的突触核蛋白病，然而，它们的临床症状存在重叠。不同的疾病特征被认为是由α-突触核蛋白（α-Syn）聚集体的不同构象决定的，这些聚集体可以通过类朊病毒机制在细胞间自我传播和扩散。本研究的目的是调查使用种子扩增分析（SAA）从LBD和MSA患者的脑和脑脊液样本中扩增出的α-Syn聚集体是否保持与源自患者大脑的α-Syn聚集体相似的α-Syn播种特性。为了解决这个问题，来自LBD和MSA患者大脑的SAA扩增和未扩增的α-Syn聚集体，以及来自LBD和MSA患者脑脊液样本的SAA扩增的α-Syn聚集体，被用于处理突触核蛋白生物传感器细胞，并通过共聚焦显微镜分析诱导的细胞内α-Syn包涵体。我们的数据表明，在α-Syn生物传感器细胞中，来自LBD和MSA患者大脑的诱导α-Syn聚集体具有与从LBD和MSA患者大脑中扩增出的聚集体以及从LBD和MSA患者脑脊液样本中扩增出的聚集体相似的播种特性和形态特征。在本研究中，我们证明，无论聚集体的来源如何，来自LBD和MSA的种子都会产生具有不同形态的α-Syn细胞内积累，证实了LBD和MSA中存在不同构象的α-Syn菌株，并使我们能够根据聚集体的形态和播种特性区分突触核蛋白病。
