Proteostasis Disturbances and Inflammation in Neurodegenerative Diseases

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.

Anti-Oxidative, Anti-Inflammatory and Anti-Apoptotic Effects of Flavonols: Targeting Nrf2, NF-κB and p53 Pathways in Neurodegeneration

“…Subsequently, protein accumulation leads to widespread microglial activation and triggers the activation of inflammatory pathways and release of pro-inflammatory mediators, which, in turn, further increases ROS generation, OS, protein aggregation and neuronal damage. In this vicious cycle, degradation of misfolded proteins and damaged organelles by the ubiquitin/proteasome system and autophagy is also impaired [5,6,8,10,[26][27][28][29][30]. Regarding oxidative damage of lipid molecules, increased production of 4-hydroxy-2-nonenal (HNE), an end product of lipid peroxidation, prevents removal of glutamate by inhibiting glutamate transporters, which together with the ATP depletion, promotes glutamate-mediated excitotoxicity and increases nitric oxide (NO) production.…”

“…Neuroinflammation exacerbates impairment of neuronal functioning and speeds up synaptic and neuronal loss, development of symptoms and progression of disease. Chronic inflammation is driven by the activation and proliferation of resident microglial cells, the major component of the innate immune response in the brain, and, to a lesser extent, by reactive astrogliosis [5,6,27,29,56]. In general, the inflammatory response in neurodegenerative diseases should represent a protective mechanism aimed to reduce further damage of the brain tissue.…”

“…In general, the inflammatory response in neurodegenerative diseases should represent a protective mechanism aimed to reduce further damage of the brain tissue. Microglial cells should be essential for maintaining brain homeostasis by removing cellular debris and initiating tissue repair, but overactivation of microglial cells initiates an unregulated pro-inflammatory response that promotes tissue injury [29,57]. Under pathophysiological conditions, activated microglia may differentiate into a continuum of states between phenotypically polarized M1 and M2 states.…”

Thermodynamics and Inflammation: Insights into Quantum Biology and Ageing

“…Critically, chronic inflammation can lead to dysregulated proteostasis due to excessive ROS production, which in turn, can further drive the inflammatory process. This is well described to be part of the pathological process in neurodegeneration [99]. The link between ageing and inflammation is, thus, strong and is associated with telomere shortening and epigenetics [100,101].…”

Dietary Polyphenols in Metabolic and Neurodegenerative Diseases: Molecular Targets in Autophagy and Biological Effects

“…Dysfunction of autophagy contributes to protein misfolding and aggregation which underly the pathogenesis of human proteinopathies such as Alzheimer (AD), Parkinson (PD), and Huntington diseases [126]. Protein homeostasis is essential for the cell function but it is especially relevant in postmitotic neurons, which have a limited regenerative potential and thus, mechanisms involved in the elimination of damaged organelles or protein aggregates are crucial for preserving cell survival [127]. Although the mechanisms that control the above cited diseases are different, they share a common feature which is the accumulation of different protein aggregates in neurons, leading to cell toxicity and neurodegeneration.…”