Unfolded protein stress in the endoplasmic reticulum and mitochondria: a role in neurodegeneration

Abstract

Protein-folding occurs in several intracellular locations including the endoplasmic reticulum and mitochondria. In normal conditions there is a balance between the levels of unfolded proteins and protein folding machinery. Disruption of homeostasis and an accumulation of unfolded proteins trigger stress responses, or unfolded protein responses (UPR), in these organelles. These pathways signal to increase the folding capacity, inhibit protein import or expression, increase protein degradation, and potentially trigger cell death. Many aging-related neurodegenerative diseases involve the accumulation of misfolded proteins in both the endoplasmic reticulum and mitochondria. The exact participation of the UPRs in the onset of neurodegeneration is unclear, but there is significant evidence for the alteration of these pathways in the endoplasmic reticulum and mitochondria. Here we will discuss the involvement of endoplasmic reticulum and mitochondrial stress and the possible contributions of the UPR in these organelles to the development of two neurodegenerative diseases, Parkinson's disease (PD) and Alzheimer's disease (AD).

Keywords: Alzheimer's disease; Parkinson's disease; endoplasmic reticulum; mitochondria; neurodegeneration; unfolded protein response.

Figure 1

The Unfolded Protein Response in the ER. Several environment alterations including changes in the cellular redox state, calcium concentration, ATP concentration, and inhibition of protein glycosylation affect the protein folding capacity of the ER. Three transmembrane ER receptors, IRE1, ATF6, and PERK, sense unfolded proteins in the lumen of the ER and promote the transcription of genes whose protein products increase the folding capacity of the cell: ER chaperones [BIP, calnexin, protein disulfide isomerase (PDI), and calreticulin], ER biosynthetic machinery, and components of the ERAD degradation pathway.

Figure 2

The induction of apoptosis by the ER and mitochondria. Prolonged ER stress triggers apoptosis by mitochondria-dependent and independent mechanisms. IRE1 and PERK signaling can induce apoptosis in a mitochondria-dependent manner by activating the expression of anti-apoptotic BCL 2 family proteins (green box) and inhibiting the expression of pro-apoptotic BCL 2 family members (red box). Although the mechanism is unclear, the regulation of BCL 2 family members precipitates the post-translational activation of the ER-localized BCL 2 family members BAK and BAX (dashed line), which re-localize to the mitochondria and lead to caspase activation and the release of pro-apoptotic signals such as cytochrome c. The release of calcium from the ER induces the cleavage of the ER membrane-associated caspase 12 and the activation of the caspase cascade that promotes apoptosis in a mitochondria-independent manner.

Figure 3

Model of the mitochondrial Unfolded Protein Response (MT-UPR). Misregulation of import of nuclearly encoded mitochondrial proteins, misregulation of mitochondrial gene expression or damage of mtDNA or mitochondrially localized proteins can cause the accumulation of misfolded or damaged proteins leading to mitochondrial stress. The MT-UPR pathway is thought to restore protein folding homeostasis in MT. This pathway has been described in mammalian cells and in C. elegans. Proteins shown in gray are shared between the two models. Proteins in yellow are unique to the mammalian model and proteins in green have only been described in C. elegans.

Figure 4

Model for roles of unfolded protein stress in neurodegeneration. Under unmitigated stress, as may be the case in many neurodegenerative diseases, the ER-UPR can induce cell death. The disruption or malfunction of the ER-UPR may also contribute to the development of important pathologies like neurodegenerative diseases. Although the data is unclear, the ER-UPR may induce mitochondrial stress (dashed line) through calcium signaling or other means. Mitochondrial stress is well known to induce apoptosis and contribute to neurodegeneration. We propose a model in which the MT-UPR stimulated by protein misfolding that is characteristic of neurodegenerative diseases may also play a role in cell death (dashed line).