Abstract
Protein homeostasis (proteostasis) disturbances and inflammation are evident in normal aging and some age-related neurodegenerative diseases. While the proteostasis network maintains the integrity of intracellular and extracellular functional proteins, inflammation is a biological response to harmful stimuli. Cellular stress conditions can cause protein damage, thus exacerbating protein misfolding and leading to an eventual overload of the degradation system. The regulation of proteostasis network is particularly important in postmitotic neurons due to their limited regenerative capacity. Therefore, maintaining balanced protein synthesis, handling unfolding, refolding, and degrading misfolded proteins are essential to preserve all cellular functions in the central nervous sysytem. Failing proteostasis may trigger inflammatory responses in glial cells, and the consequent release of inflammatory mediators may lead to disturbances in proteostasis. Here, we review the mechanisms of proteostasis and inflammatory response, emphasizing their role in the pathological hallmarks of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Furthermore, we discuss the interplay between proteostatic stress and excessive immune response that activates inflammation and leads to dysfunctional proteostasis.
Highlights
We have reviewed the current research related to the relationship between proteostasis disturbances and inflammatory response in neurodegenerative diseases
A growing body of evidence shows that protein misfolding, aggregation, and aberrant modifications can lead to excessive immune responses causing neuroinflammation, which is associated with neurodegenerative diseases
Reactive glial cells in the central nervous system (CNS) play an important role in deleterious non-cell-autonomous mechanisms leading to the loss of proteostasis
Summary
Inflammation and the disruption of proteostasis manifest upon normal aging and in some age-related neurodegenerative diseases. The two main protein degradation systems are the ubiquitin–proteasome system (UPS), which is responsible for the degradation of both functional and dysfunctional short-lived proteins coupled with ubiquitin molecules [7,8], and the autophagy-lysosomal system that degrades long-lived proteins, large aggregates of proteins, cellular components and organelles through the lysosomal compartment [9] In this part of the review, we describe how inflammation causes proteostasis disturbances through. Mediators of oxidative stress and inflammation are in balance with the counteracting detoxifying and anti-inflammatory molecules This balance is disturbed in some pathological states, and it is shifted toward the oxidative stress and pro-inflammatory direction, leading to DNA and protein damage, inflammation, and neuronal cell death. ROS and RNS Cause Protein Oxidative Modification Leading to Protein Misfolding
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