Dataset Information

Unfolded Protein Response and Macroautophagy in Alzheimer's, Parkinson's and Prion Diseases.

ABSTRACT: Proteostasis are integrated biological pathways within cells that control synthesis, folding, trafficking and degradation of proteins. The absence of cell division makes brain proteostasis susceptible to age-related changes and neurodegeneration. Two key processes involved in sustaining normal brain proteostasis are the unfolded protein response and autophagy. Alzheimer's disease (AD), Parkinson's disease (PD) and prion diseases (PrDs) have different clinical manifestations of neurodegeneration, however, all share an accumulation of misfolded pathological proteins associated with perturbations in unfolded protein response and macroautophagy. While both the unfolded protein response and macroautophagy play an important role in the prevention and attenuation of AD and PD progression, only macroautophagy seems to play an important role in the development of PrDs. Macroautophagy and unfolded protein response can be modulated by pharmacological interventions. However, further research is necessary to better understand the regulatory pathways of both processes in health and neurodegeneration to be able to develop new therapeutic interventions.

SUBMITTER: Milisav I

PROVIDER: S-EPMC6332363 | biostudies-other | 2015 Dec

REPOSITORIES: biostudies-other

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Unfolded Protein Response and Macroautophagy in Alzheimer's, Parkinson's and Prion Diseases.

Milisav Irina I Šuput Dušan D Ribarič Samo S

Molecules (Basel, Switzerland) 20151218 12

Proteostasis are integrated biological pathways within cells that control synthesis, folding, trafficking and degradation of proteins. The absence of cell division makes brain proteostasis susceptible to age-related changes and neurodegeneration. Two key processes involved in sustaining normal brain proteostasis are the unfolded protein response and autophagy. Alzheimer's disease (AD), Parkinson's disease (PD) and prion diseases (PrDs) have different clinical manifestations of neurodegeneration, ...[more]

PMID: 26694349

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Project description:BackgroundNonalcoholic fatty liver disease (NAFLD) is a known outcome of hepatosteatosis. Free fatty acids (FFA) induce the unfolded protein response (UPR) or endoplasmic reticulum (ER) stress that may induce apoptosis. Recent data indicate ER stress to be a major player in the progression of fatty liver to more aggressive lesions. Autophagy on the other hand has been demonstrated to be protective against ER stress-induced cell death. We hypothesized that exendin-4 (GLP-1 analog) treatment of fat loaded hepatocytes can reduce steatosis by autophagy which leads to reduced ER stress-related hepatocyte apoptosis.Methodology/principal findingsPrimary human hepatocytes were loaded with saturated, cis- and trans-unsaturated fatty acids (palmitic, oleic and elaidic acid respectively). Steatosis, induced with all three fatty acids, was significantly resolved after exendin-4 treatment. Exendin-4 sustained levels of GRP78 expression in fat-loaded cells when compared to untreated fat-loaded cells alone. In contrast, CHOP (C/EBP homologous protein); the penultimate protein that leads to ER stress-related cell death was significantly decreased by exendin-4 in hepatocytes loaded with fatty acids. Finally, exendin-4 in fat loaded hepatocytes clearly promoted gene products associated with macroautophagy as measured by enhanced production of both Beclin-1 and LC3B-II, markers for autophagy; and visualized by transmission electron microscopy (TEM). Similar observations were made in mouse liver lysates after mice were fed with high fat high fructose diet and treated with a long acting GLP-1 receptor agonist, liraglutide.Conclusions/significanceGLP-1 proteins appear to protect hepatocytes from fatty acid-related death by prohibition of a dysfunctional ER stress response; and reduce fatty acid accumulation, by activation of both macro-and chaperone-mediated autophagy. These findings provide a novel role for GLP-1 proteins in halting the progression of more aggressive lesions from underlying steatosis in humans afflicted with NAFLD.

Dataset Information

Unfolded Protein Response and Macroautophagy in Alzheimer's, Parkinson's and Prion Diseases.

Publications

Unfolded Protein Response and Macroautophagy in Alzheimer's, Parkinson's and Prion Diseases.

Similar Datasets

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