REST alleviates neurotoxic prion peptide-induced synaptic abnormalities, neurofibrillary degeneration and neuronal death partially via LRP6-mediated Wnt-β-catenin signaling

Abstract

Prion diseases are a group of infectious neurodegenerative diseases characterized by multiple neuropathological hallmarks including synaptic damage, spongiform degeneration and neuronal death. The factors and mechanisms that maintain cellular morphological integrity and protect against neurodegeneration in prion diseases are still unclear. Here we report that after stimulation with the neurotoxic PrP106-126 fragment in primary cortical neurons, REST translocates from the cytoplasm to the nucleus and protects neurons from harmful effects of PrP106-126. Overexpression of REST reduces pathological damage and abnormal biochemical alterations of neurons induced by PrP106-126 and maintains neuronal viability by stabilizing the level of pro-survival protein FOXO1 and inhibiting the permeability of the mitochondrial outer membrane, release of cytochrome c from mitochondria to cytoplasm and the activation of Capase3. Conversely, knockdown of REST exacerbates morphological damage and inhibits the expression of FOXO1. Additionally, by overexpression or knockdown of LRP6, we further show that LRP6-mediated Wnt-β-catenin signaling partly regulates the expression of REST. Collectively, we demonstrate for the first time novel neuroprotective function of REST in prion diseases and hypothesise that the LRP6-Wnt-β-catenin/REST signaling plays critical and collaborative roles in neuroprotection. This signaling of neuronal survival regulation could be explored as a viable therapeutic target for prion diseases and associated neurodegenerative diseases.

PRAS40 alleviates neurotoxic prion peptide‐induced apoptosis via mTOR‐AKT signaling

“…Misfolded proteins evoke oxidative stress, which contributes to the development of apoptotic neuronal cell death and neuronal dysfunction . PrP 106‐126 induced mitochondrial dysfunction and apoptosis in N2a cells, consistent with our previous work . Apoptosis is a complex process of programmed cell death and destruction that is involved in many diseases and disorders .…”

“…[14][15][16][17] PrP 106-126 induced mitochondrial dysfunction and apoptosis in N2a cells, consistent with our previous work. 55,56 Apoptosis is a complex process of programmed cell death and destruction that is involved in many diseases and disorders. 57 In many types of cancer, resistance to apoptosis is a major driver of pathogenesis.…”

Downregulation of the Repressor Element 1-Silencing Transcription Factor (REST) Is Associated with Akt-mTOR and Wnt-β-Catenin Signaling in Prion Diseases Models

“…We previously found that overexpression of REST alleviated PrP106-126-induced excess autophagosomes or autophagolysosomes in PCCN (Song et al, 2016). To examine the relationship of REST and autophagy in the cortex, brain sections of normal and 263K-infected hamsters were double-stained with antibodies to REST and LC3-II (a marker of cellular autophagosomes).…”

“…We previously reported that REST was induced and translocated from the cytoplasm to the nucleus in PCCN upon exposure to the prion peptide but failed to function as a neuroprotective factor with continued stimulation by PrP106-126 (Song et al, 2016). Here we further demonstrated that REST is lost from the nucleus in the brains of scrapie-infected hamsters and taken up in autophagosomes.…”

Calcium-dependent serine-threonine phosphatase, calcineurin inactivation mediated by baicalein attenuates prion protein-mediated neuronal cell damage

“…PrP C is soluble, with a predominant alpha-helical conformation, but a disease-causing, infectious form (PrP Sc ) is insoluble, βsheet-rich, and protease-resistant [5]. Because of β-sheet-rich conformation, PrP Sc is highly pathogenic and neurotoxic when compared with the largely α-sheet-rich structure of PrP C [6,7]. PrP Sc is a misfolded protein aggregate accumulating within endosomes or on the neuronal cell surface.…”