Rolle Irene Giulia, Burato Anna, Bacınoğlu Merve Begüm, Moda Fabio, Legname Giuseppe
Laboratory of Prion Biology, Department of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati (SISSA), 34136 Trieste, Italy.
Unit of Laboratory of Medicine, Laboratory of Clinical Pathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy.
Viruses. 2025 Jun 29;17(7):928. doi: 10.3390/v17070928.
The cellular prion protein (PrP) is studied in prion diseases, where its misfolded isoform (PrP) leads to neurodegeneration. PrP has also been implicated in several physiological functions. The protein is abundant in the nervous system, and it is critical for cell signaling in cellular communication, where it acts as a scaffold for various signaling molecules. The Reelin signaling pathway, implicated both in Alzheimer's and prion diseases, engages Dab1, an adaptor protein influencing APP processing and amyloid beta deposition. Here, we show, using knockout models (), that PrP modulates Reelin signaling, affecting Dab1 activation and downstream phosphorylation in both neuronal cultures and mouse brains. Notably, mice showed reduced responsiveness to Reelin, associated with altered Dab1 phosphorylation and Fyn kinase activity. Even though no direct interaction between PrP and Reelin/ApoER2 was found, neurons showed lower NCAM levels, a well-established PrP interactor. Prion infection further disrupted the Reelin signaling pathway, thus downregulating Dab1 and Reelin receptors and altering Reelin processing, like Alzheimer's disease pathology. These findings emphasize PrP indirect role in Dab1 signaling via the NCAM and Fyn pathways, which influence synaptic function and neurodegeneration in prion diseases.
细胞朊蛋白（PrP）在朊病毒疾病中受到研究，在该疾病中其错误折叠的异构体（PrP）会导致神经退行性变。PrP还与多种生理功能有关。该蛋白在神经系统中含量丰富，在细胞通讯中的细胞信号传导中起关键作用，它作为各种信号分子的支架。与阿尔茨海默病和朊病毒疾病都有关的Reelin信号通路涉及Dab1，一种影响APP加工和淀粉样β沉积的衔接蛋白。在此，我们使用基因敲除模型表明，PrP调节Reelin信号传导，影响神经元培养物和小鼠大脑中的Dab1激活及下游磷酸化。值得注意的是，基因敲除小鼠对Reelin的反应性降低，这与Dab1磷酸化和Fyn激酶活性改变有关。尽管未发现PrP与Reelin/ApoER2之间存在直接相互作用，但基因敲除神经元显示出较低的NCAM水平，NCAM是一种已明确的PrP相互作用蛋白。朊病毒感染进一步破坏了Reelin信号通路，从而下调Dab1和Reelin受体并改变Reelin加工，类似于阿尔茨海默病的病理情况。这些发现强调了PrP通过NCAM和Fyn途径在Dab1信号传导中的间接作用，这会影响朊病毒疾病中的突触功能和神经退行性变。
