Autophagy induced by the class III histone deacetylase Sirt1 prevents prion peptide neurotoxicity

Lee

et al. 2017

IJN

Self Cite

Graphene oxide (GO) is a nanomaterial with newly developing biological applications. Autophagy is an intracellular degradation system that has been associated with the progression of neurodegenerative disorders. Although induction of autophagic flux by GO has been reported, the underlying signaling pathway in neurodegenerative disorders and how this is involved in neuroprotection remain obscure. We show that GO itself activates autophagic flux in neuronal cells and confers a neuroprotective effect against prion protein (PrP) (106-126)-mediated neurotoxicity. GO can be detected in SK-N-SH neuronal cells, where it triggers autophagic flux signaling. GO-induced autophagic flux prevented PrP (106-126)-induced neurotoxicity in SK-N-SH cells. Moreover, inactivation of autophagic flux blocked GO-induced neuroprotection against prion-mediated mitochondrial neurotoxicity. This is the first study to demonstrate that GO regulates autophagic flux in neuronal cells, and that activation of autophagic flux signals, induced by GO, plays a neuroprotective role against prion-mediated mitochondrial neurotoxicity. These results suggest that the nanomaterial GO may be used to activate autophagic flux and could be used in neuroprotective strategies for treatment of neurodegenerative disorders, including prion diseases.

Section: Go Protects Sk-n-sh Cells Against Prp (106-126)-mediated Apomentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Autophagic flux induced by graphene oxide has a neuroprotective effect against human prion protein fragments

Lee

et al. 2017

IJN

Self Cite

“…The contention that SIRT1 promotes autophagy was supported by a number of subsequent reports. [87][88][89][90] Remarkably, however, several other reports have appeared showing that SIRT1 inhibits autophagy. [91][92][93] Our own work with primary fibroblasts and neurons derived from our Sirt1 -/-and Sirt1 Y/Y mice showed no defect in autophagy induced by glucose deprivation (Caron et al, unpublished).…”

Section: Monographsmentioning

confidence: 99%

SIRT1 is a Highly Networked Protein That Mediates the Adaptation to Chronic Physiological Stress

et al. 2013

SIRT1 is a NAD + -dependent protein deacetylase that has a very large number of established protein substrates and an equally impressive list of biological functions thought to be regulated by its activity. Perhaps as notable is the remarkable number of points of conflict concerning the role of SIRT1 in biological processes. For example, evidence exists suggesting that SIRT1 is a tumor suppressor, is an oncogene, or has no effect on oncogenesis. Similarly, SIRT1 is variably reported to induce, inhibit, or have no effect on autophagy. We believe that the resolution of many conflicting results is possible by considering recent reports indicating that SIRT1 is an important hub interacting with a complex network of proteins that collectively regulate a wide variety of biological processes including cancer and autophagy. A number of the interacting proteins are themselves hubs that, like SIRT1, utilize intrinsically disordered regions for their promiscuous interactions. Many studies investigating SIRT1 function have been carried out on cell lines carrying undetermined numbers of alterations to the proteins comprising the SIRT1 network or on inbred mouse strains carrying fixed mutations affecting some of these proteins. Thus, the effects of modulating SIRT1 amount and/or activity are importantly determined by the genetic background of the cell (or the inbred strain of mice), and the effects attributed to SIRT1 are synthetic with the background of mutations and epigenetic differences between cells and organisms. Work on mice carrying alterations to the Sirt1 gene suggests that the network in which SIRT1 functions plays an important role in mediating physiological adaptation to various sources of chronic stress such as calorie restriction and calorie overload. Whether the catalytic activity of SIRT1 and the nuclear concentration of the co-factor, NAD + , are responsible for modulating this activity remains to be determined. However, the effect of modulating SIRT1 activity must be interpreted in the context of the cell or tissue under investigation. Indeed, for SIRT1, we argue that context is everything.

“…Activating Sirt1 induces autophagy, and activated autophagy protects neurons against prion diseases by regulating mitochondrial homeostasis. The underlying mechanism is associated with a decrease of the mitochondrial membrane potential value, and a reduction for PrP fragment (106-126)-induced Bax translocation to the mitochondria and cytochrome c release into the cytosol, as Sirt1 overexpression is mediated by adenoviral vector [76]. Further study proved that resveratrol, the Sirt1 activator, is important in attenuating cellular injury and oxidative stress that prevents PrP (106-126)-induced neuronal cell death, and blocks neurotoxicity by activating autophagy through the autophagy-lysosome pathway [77].…”

Section: Autophagy In Prion Diseasesmentioning

confidence: 99%

Role of autophagy in prion protein-induced neurodegenerative diseases

Yao¹,

Zhao²,

Khan³

et al. 2013

ABBS

Prion diseases, characterized by spongiform degeneration and the accumulation of misfolded and aggregated PrP Sc in the central nervous system, are one of fatal neurodegenerative and infectious disorders of humans and animals. In earlier studies, autophagy vacuoles in neurons were frequently observed in neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's diseases as well as prion diseases. Autophagy is a highly conserved homeostatic process by which several cytoplasmic components ( proteins or organelles) are sequestered in a doublemembrane-bound vesicle termed 'autophagosome' and degraded upon their fusion with lysosome. The pathway of intercellular self-digestion at basal physiological levels is indispensable for maintaining the healthy status of tissues and organs. In case of prion infection, increasing evidence indicates that autophagy has a crucial ability of eliminating pathological PrP Sc accumulated within neurons. In contrast, autophagy dysfunction in affected neurons may contribute to the formation of spongiform changes. In this review, we summarized recent findings about the effect of mammalian autophagy in neurodegenerative disorders, particularly in prion diseases. We also summarized the therapeutic potential of some small molecules (such as lithium, rapamycin, Sirtuin 1 and resveratrol) targets to mitigate such diseases on brain function. Furthermore, we discussed the controversial role of autophagy, whether it mediates neuronal toxicity or serves a protective function in neurodegenerative disorders.