Autophagy and Cell Death in Alzheimer’s, Parkinson’s and Prion Diseases

Abstract

Neurodegenerative brain disorders (NBD) impair brain cells' proteostasis with the accumulation of normal, mutant, misfolded or unfolded proteins in the endoplasmic reticulum (ER). The increased ER burden of these proteins elicits the unfolded protein response (UPR) and stimulates autophagy (AUT). In the short term, UPR and AUT attenuate ER's burden. With prolonged ER stress, the UPR changes from supporting cell survival to promoting apoptosis. The failure of the UPR, to meet the increased protein burden, leads to an increase in cytosolic protein accumulation that initially further stimulates AUT. Over time, the accumulated proteins in the cytosol undergo post-translational changes into toxic monomers and oligomers that repress AUT at multiple levels and promote cell death. This review describes the interlinked signalling pathways of AUT, apoptosis and necroptosis and their modulation by Alzheimer's, Parkinson's and prion diseases and outlines the pharmacological strategies for targeting AUT, apoptosis and necroptosis signalling pathways. 2 oligomers; their production is stimulated by chronic inflammation and increased reactive oxygen species (ROS) production. These monomers and oligomers repress AUT and trigger either apoptosis or necroptosis (Figure 1) [4, 6-8]. Autophagy changes in selected NBDAn efficient autophagy (AUT) delays or attenuates the progression of AD, PD and PrD [9][10][11][12]. A summary of AUT changes in selected NBD is shown in Figure 2. Post-translationally modified proteins (PTMP)-such as soluble amyloid β-peptide 42 with a single oxidised methionine residue at position 35 (Aβ42-MET35-OX) in Alzheimer's disease, alpha-synuclein oxidised on methionine residues (MET-OX-αSYN) in Parkinson's disease and oxidised, self-propagating infectious isoforms of prion protein (MET-OX-PRP Sc ) in prion diseases (PrD)-inhibit (a) AUT, in AD, PD and PrD, and also (b) mitochondrial (MITO) function [13-23]. MET-OX-PRP Sc indirectly damage MITO function. The normal prion protein (PrP c ) binds with

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“…In addition, this could be due to the expression of cell survival signaling like the BCL-2 family. Pretreatment with alphamangostin downregulated pro-apoptotic BAX and restored antiapoptotic BCL-2 which inhibit the formation of MPTP, block the release of cytochrome c, and ultimately suppress the caspase cascade (28)(29)(30)(31).…”

“…Apoptosis is a terminal cellular event that is promoted by the BCL-2 superfamily of cell death regulators, such as BAX and BCL-2, which initiate the caspase cascade and eventually result in cell death via enzymatic destruction of cytoplasmic proteins and DNA (28,29). To further investigate the mechanism of alpha-mangostin on oxidative stress, protein expressions of the BCL-2 family were elucidated by Western blot analysis.…”

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