血浆中的α-突触核蛋白构象可区分帕金森病与路易体痴呆。

α-Synuclein Conformations in Plasma Distinguish Parkinson's Disease from Dementia with Lewy Bodies.

作者信息

Kannarkat George T, Zack Rebecca, Skrinak R Tyler, Morley James F, Davila-Rivera Roseanne, Arezoumandan Sanaz, Dorfmann Katherine, Luk Kelvin, Wolk David A, Weintraub Daniel, Tropea Thomas F, Lee Edward B, Xie Sharon X, Chandrasekaran Ganesh, Lee Virginia M-Y, Irwin David, Akhtar Rizwan S, Chen-Plotkin Alice S

机构信息

Department of Neurology, Perelman School of Medicine, University of Pennsylvania; Philadelphia, PA, USA, 19104.

Parkinson's Disease Research, Education and Clinical Center, Corporal Michael J. Crescenz VA Medical Center; Philadelphia, PA, USA, 19104.

出版信息

Res Sq. 2024 Sep 17:rs.3.rs-5033901. doi: 10.21203/rs.3.rs-5033901/v1.

DOI:10.21203/rs.3.rs-5033901/v1

PMID:39372921

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11451739/

Abstract

Aggregation of misfolded α-synuclein (aSyn) within the brain is the pathologic hallmark of Lewy body diseases (LBD), including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Evidence exists for aSyn "strains" - conformations with distinct biological properties. However, biomarkers for PD vs. DLB, including potential aSyn strain differences, are lacking. Here, we used two monoclonal antibodies selective for different aSyn species - termed Strain A and B - to evaluate human brain tissue, cerebrospinal fluid (CSF), and plasma. Surprisingly, levels of Strain A and B aSyn species differed in plasma from individuals with PD vs. DLB in two independent cohorts. Lower plasma aSyn Strain A species also predicted subsequent PD cognitive decline. Strain A and Strain B aSyn species were undetectable in CSF, but plasma aSyn species could template aSyn fibrillization, particularly in PD. Our findings suggest that aSyn strains may impact LBD clinical presentation and originate outside the brain.

摘要

错误折叠的α-突触核蛋白（aSyn）在脑内的聚集是路易体病（LBD）的病理标志，包括帕金森病（PD）和路易体痴呆（DLB）。有证据表明存在aSyn“毒株”——具有不同生物学特性的构象。然而，缺乏区分PD与DLB的生物标志物，包括潜在的aSyn毒株差异。在此，我们使用两种对不同aSyn种类具有选择性的单克隆抗体——称为毒株A和B——来评估人脑组织、脑脊液（CSF）和血浆。令人惊讶的是，在两个独立队列中，PD患者与DLB患者血浆中的毒株A和B aSyn种类水平存在差异。较低的血浆aSyn毒株A种类水平也预示着随后的PD认知衰退。在CSF中未检测到毒株A和毒株B aSyn种类，但血浆aSyn种类可促使aSyn纤维化，尤其是在PD中。我们的研究结果表明，aSyn毒株可能影响LBD的临床表现，且起源于脑外。