Abstract
Prion diseases are a group of infectious diseases characterized by multiple neuropathological changes, yet the mechanisms that preserve function and protect against prion-associated neurodegeneration are still unclear. We previously reported that the repressor element 1-silencing transcription factor (REST) alleviates neurotoxic prion peptide (PrP106-126)-induced toxicity in primary neurons. Here we confirmed the findings of the in vitro model in 263K infected hamsters, an in vivo model of prion diseases and further showed the relationships between REST and related signaling pathways. REST was depleted from the nucleus in prion infected brains and taken up by autophagosomes in the cytoplasm, co-localizing with LC3-II. Importantly, downregulation of the Akt–mTOR and at least partially inactivation of LRP6-Wnt-β-catenin signaling pathways correlated with the decreased levels of REST in vivo in the brain of 263K-infected hamsters and in vitro in PrP106-126-treated primary neurons. Overexpression of REST in primary cortical neurons alleviated PrP106-126 peptide-induced neuronal oxidative stress, mitochondrial damage and partly inhibition of the LRP6-Wnt-β-catenin and Akt–mTOR signaling. Based on our findings, a model of REST-mediated neuroprotection in prion infected animals is proposed, with Akt–mTOR and Wnt-β-catenin signaling as the key pathways. REST-mediated neuronal survival signaling could be explored as a viable therapeutic target for prion diseases and related neurodegenerative diseases.
Highlights
Prion is a protein-conformation-based infectious agent (Zhang et al, 2014; Wang et al, 2015) and causes transmissible spongiform encephalopathies (TSEs) in animals and humans (Wadsworth and Collinge, 2011)
In line with a previous in vitro study (Song et al, 2016), repressor element 1-silencing transcription factor (REST) markedly declined in the brain of 263K-infected hamsters at the terminal stage compared with the normal control
Cortex, cerebellum, hippocampus and medulla oblongata were immunohistochemically (IHC) studied for the expression of REST (Figure 2) and stained with haematoxylin and eosin (H&E) (Figure 3A, left panel) for observing and confirming brain lesions induced by 263K scrapie (Shah et al, 2017)
Summary
Prion is a protein-conformation-based infectious agent (Zhang et al, 2014; Wang et al, 2015) and causes transmissible spongiform encephalopathies (TSEs) in animals and humans (Wadsworth and Collinge, 2011). The neuropathology of prion diseases is characterized by synaptic alterations, spongiform degeneration, neuronal cell death, reactive gliosis, and amyloid plaque formation. Our recent study indicated that the transcription factor REST, a RE1-silencing transcription factor may function as a neuroprotector in prion diseases (Song et al, 2016). REST protein protects aging neurons from death by repressing genes that promote cell death and Alzheimer’s disease (AD) pathology and inducing the expression of stress response genes (Lu et al, 2014). REST alleviates neurotoxic prion peptide (PrP106-126)induced synaptic abnormalities, neurofibrillary degeneration and neuronal death partially via the low-density lipoprotein receptorrelated protein 6 (LRP6)-mediated Wnt-β-catenin signaling in primary cortical neurons (Song et al, 2016). Overexpression of REST protects neurons through upregulated expression of postsynaptic protein, stabilized level of pro-survival protein and suppressed pro-apoptotic protein (Song et al, 2016)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
