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).

Mitochondrial Signaling: Forwards, Backwards, and In Between

“…This results in activation of NRF1 and other cytoprotective responses to overcome the mitochondrial stress. Additionally, disruptions in unfolded protein responses in both ER and mitochondria have been implicated in the development of neurodegenerative diseases such as Parkinson's and Alzheimer's diseases among others [56, 57]. …”

Unfolded protein response signaling by transcription factor XBP‐1 regulates ADAM10 and is affected in Alzheimer's disease

“…This transcription factor displayed a strong effect on the ratio of ADAM10‐ to BACE‐1‐promoter activity in our screening approach, and UPR has already been correlated to neurodegenerative disease in recently rising numbers of publications (reviewed in ref. 16). We investigated the underlying mechanism of ADAM10 regulation by XBP‐1 in cell culture and demonstrate the consistency of our findings by quantitative analysis of mRNA from 2 AD mouse models and cortical tissue of AD postmortem samples.…”

Lack of GCN5 remarkably enhances the resistance against prolonged endoplasmic reticulum stress-induced apoptosis through up-regulation of Bcl-2 gene expression

“…Bcl-2 family can play important roles in prolonged ER stressinduced apoptosis [5,10,30]. In our previous reports [19,22], we showed that the mRNA level of Bcl-2, an anti-apoptotic gene, was drastically increased in DGCN5.…”

“…Alzheimer's disease, amyotrophic lateral sclerosis and Parkinson's disease) [5,6] and diabetes [7,8]. Prolonged ER stress could trigger apoptotic cell death through various signal transduction pathways [5,9,10]. Upon chronic ER stress, caspase-12, the ER membrane associated protease belonging to the caspase family, is activated, followed by promoting apoptosis via initiating caspasemediated limited proteolysis cascade [11].…”

“…Catastrophe of these functions would lead to ER stress that causes various diseases such as cancer [4], neurodegenerative diseases (e.g. Alzheimer's disease, amyotrophic lateral sclerosis and Parkinson's disease) [5,6] and diabetes [7,8]. Prolonged ER stress could trigger apoptotic cell death through various signal transduction pathways [5,9,10].…”