Cui Shiquan, Zhang Tingting, Xiong Xinrui, Zhao Jihe, Cao Qilin, Zhou Hongxia, Xia Xu-Gang
Department of Environmental Health Sciences, Robert Stempel College of Public Health & Social Work, Florida International University, Miami, FL, United States.
Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, Orlando, FL, United States.
Front Neurosci. 2023 Sep 25;17:1279259. doi: 10.3389/fnins.2023.1279259. eCollection 2023.
Accumulating evidence suggests a gain of elusive toxicity in pathogenically mutated PFN1. The prominence of PFN1 aggregates as a pivotal pathological hallmark in PFN1 transgenic rats underscores the crucial involvement of protein aggregation in the initiation and progression of neurodegeneration. Detergent-insoluble materials were extracted from the spinal cords of paralyzed rats afflicted with ALS and were intramuscularly administered to asymptomatic recipient rats expressing mutant PFN1, resulting in an accelerated development of PFN1 inclusions and ALS-like phenotypes. This effect diminished when the extracts derived from wildtype PFN1 transgenic rats were employed, as detergent-insoluble PFN1 was detected exclusively in mutant PFN1 transgenic rats. Consequently, the factor influencing the progression of ALS pathology in recipient rats is likely associated with the presence of detergent-insoluble PFN1 within the extracted materials. Noteworthy is the absence of disease course modification upon administering detergent-insoluble extracts to rats that already displayed PFN1 inclusions, suggesting a seeding rather than augmenting role of such extracts in initiating neuropathological changes. Remarkably, pathogenic PFN1 exhibited an enhanced affinity for the molecular chaperone DNAJB6, leading to the sequestration of DNAJB6 within protein inclusions, thereby depleting its availability for cellular functions. These findings shed light on a novel mechanism that underscores the prion-like characteristics of pathogenic PFN1 in driving neurodegeneration in the context of PFN1-related ALS.
越来越多的证据表明，致病性突变的PFN1具有难以捉摸的毒性增加。PFN1聚集体作为PFN1转基因大鼠的关键病理标志的突出性强调了蛋白质聚集在神经退行性变的起始和进展中的关键作用。从不明原因的瘫痪大鼠脊髓中提取不溶性去污剂材料，并将其肌肉注射到表达突变型PFN1的无症状受体大鼠中，导致PFN1包涵体和ALS样表型加速发展。当使用源自野生型PFN1转基因大鼠的提取物时，这种效应减弱，因为仅在突变型PFN1转基因大鼠中检测到不溶性去污剂PFN1。因此，影响受体大鼠ALS病理学进展的因素可能与提取物中存在不溶性去污剂PFN1有关。值得注意的是，将不溶性去污剂提取物施用于已经显示PFN1包涵体的大鼠后，疾病进程没有改变，这表明此类提取物在引发神经病理变化中起种子作用而非增强作用。值得注意的是，致病性PFN1对分子伴侣DNAJB6表现出增强的亲和力，导致DNAJB6被隔离在蛋白质包涵体内，从而耗尽其用于细胞功能的可用性。这些发现揭示了一种新机制，该机制强调了致病性PFN1在PFN1相关ALS背景下驱动神经退行性变的朊病毒样特征。
