Research Article: The unfolded protein response in neurodegenerative diseases: a neuropathological perspective

Date Published: July 26, 2015

Publisher: Springer Berlin Heidelberg

Author(s): Wiep Scheper, Jeroen J. M. Hoozemans.


The unfolded protein response (UPR) is a stress response of the endoplasmic reticulum (ER) to a disturbance in protein folding. The so-called ER stress sensors PERK, IRE1 and ATF6 play a central role in the initiation and regulation of the UPR. The accumulation of misfolded and aggregated proteins is a common characteristic of neurodegenerative diseases. With the discovery of the basic machinery of the UPR, the idea was born that the UPR or part of its machinery could be involved in neurodegenerative diseases like Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and prion disease. Over the last decade, the UPR has been addressed in an increasing number of studies on neurodegeneration. The involvement of the UPR has been investigated in human neuropathology across different neurological diseases, as well as in cell and mouse models for neurodegeneration. Studies using different disease models display discrepancies on the role and function of the UPR during neurodegeneration, which can often be attributed to differences in methodology. In this review, we will address the importance of investigation of human brain material for the interpretation of the role of the UPR in neurological diseases. We will discuss evidence for UPR activation in neurodegenerative diseases, and the methodology to study UPR activation and its connection to brain pathology will be addressed. More recently, the UPR is recognized as a target for drug therapy for treatment and prevention of neurodegeneration, by inhibiting the function of specific mediators of the UPR. Several preclinical studies have shown a proof-of-concept for this approach targeting the machinery of UPR, in particular the PERK pathway, in different models for neurodegeneration and have yielded paradoxical results. The promises held by these observations will need further support by clarification of the observed differences between disease models, as well as increased insight obtained from human neuropathology.

Partial Text

Neurodegenerative disorders like Alzheimer’s disease (AD), Parkinson’s disease (PD), prion disease, Huntington’s disease (HD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS) are characterized by the accumulation and aggregation of misfolded proteins. The proteins found in the aggregates and the brain areas where they accumulate are different for each neurodegenerative disease. Like all cells, neurons have an extensive system for protein quality control. This serves to detect and remove aberrant proteins, to prevent the detrimental aggregation process and deal with misfolding early in the process. A major site of protein synthesis is the endoplasmic reticulum (ER), where secretory, transmembrane and organelle-targeted proteins are synthesized, comprising approximately 30 % of the proteome. A key component of protein quality control in the ER is the unfolded protein response (UPR), which comes into play if the protein homeostasis (proteostasis) in the ER is disturbed.

To detect UPR activation in samples of human brain, different methods can be employed. Altered expression of UPR target genes can be determined by analysis of mRNA expression in brain lysates. This is a sensitive method, but has the disadvantage that changes in only a subset of the cells may not be detected because they are diluted out. The same limitation applies to measuring protein levels of UPR markers in protein lysates. Currently, many antibodies are available directed to the main players of the UPR that enable studying its activation using different techniques. It should be noted that determination of UPR protein levels not always allows assessment of UPR activation since part of the UPR relies on mechanisms that involve protein cleavage, post-translational modification, intracellular distribution or altered conformation.

To model neurodegenerative diseases, overexpression of aggregating proteins and more often of mutant derivatives associated with familial variants of the disease is used. Typically, this models only part of the pathogenesis in an exaggerated and accelerated fashion. This is useful for some purposes, but also creates an artifact-prone situation, in particular for a response that is designed to detect protein stress. A good example of ambiguous results is Presenilin 1 (PS1), mutations in which are the most common cause of autosomal dominant inherited forms of AD. PS1 was reported to affect the signaling of the UPR in models using overexpression [48] as well as knockout [71]. In contrast, other labs did not observe effects of PS1 mutant overexpression or deficiency on the UPR [75, 87, 101]. The exact cause of these differences is not known, and may relate to different cells, promoters and expression levels, mouse lines, specific mutations in PS1 used, etc. In any case, it is clear that disturbed UPR signaling is not a common feature of PS1 mutations and, in addition, it is elusive whether UPR signaling is activated and involved in the pathogenesis of AD in PS1 mutation carriers.

Many models for neurodegenerative disease show UPR activity, but how do changes in UPR signaling affect the neurodegenerative process? This is important from mechanistic point of view, but also when considering targeting of the UPR for treatment of neurodegenerative disease.

Evidence for UPR activation can be found in patient brains as well as models of several neurodegenerative diseases. The list of small molecules that target the UPR is growing. It is however important to distinguish positive and negative effects of the UPR. This is complicated by the notion that the direction in which to interfere (stimulation or inhibition) may be strongly affected by the pathological state. Caution is therefore warranted to directly translate mechanistic observations in the physiology to an application in pathology, where the adaptive UPR may have turned maladaptive. For example, the PERK pathway is activated in several neurodegenerative diseases, in the presence or absence of activation of the other UPR pathways. The adaptive PERK pathway functions to restore ER proteostasis by reducing overall protein synthesis via phosphorylation of eIF2α and increasing the expression of UPR responsive genes via the production of the transcription factor ATF4. PERK activation increases BACE levels and thus Aβ formation. In addition, tau phosphorylation is increased if PERK is activated. The function of these transient events in the adaptive response is not fully elucidated. During prolonged UPR activation, however, aberrant Aβ and tau proteins will accumulate which will facilitate pathology and in turn may contribute to UPR activity directly or indirectly in a vicious cycle. In addition, the persistent inhibition of protein translation results in loss of synaptic proteins that are essential for neuronal function. The prolonged UPR activation in the pathological state turns the adaptive UPR maladaptive (Fig. 3). This has important implications when using intervention in this pathway as therapeutic strategy. For example, prolonged phosphorylation of eIF2α by Guanabenz or Sephin1 may be beneficial in prevention paradigms. However, in a pathological state with persistent eIF2α phosphorylation at the start of treatment this may take a turn for the worse and inhibition of the pathway is preferred, however, ISR activators like sephin1 may be beneficial in case of accumulation of ER retained proteins.Fig. 3The adaptive and maladaptive PERK pathway in neurodegenerative disease. In several neurodegenerative diseases, the PERK pathway is activated. The adaptive PERK pathway (left) functions to restore ER proteostasis. In contrast, in pathology (right) prolonged activation in neurodegenerative disease leads to loss of regulatory feedback and turns the adaptive UPR maladaptive, leading to accumulation of aberrant Aβ en tau proteins and loss of synaptic proteins. It may be beneficial to stimulate the PERK pathway (e.g., by Sephin1) in the adaptive state, however, this may worsen the situation in the pathological state. Inhibition (e.g., by GSK2606414 or ISRIB) rather than stimulation of the pathway may therefore be beneficial for neurodegenerative diseases associated with persistent UPR activation. See text for further details