The proteasome is a specialized protein complex that breaks down unwanted proteins into short peptide molecules for reuse in further protein synthesis. Any protein designated as unwanted by the addition of a ubiquitin tag can be broken down in this way. This activity is important, a form of cellular maintenance. When impaired, loss of proteasomal function allows damaged and damaging proteins to build up in the cell, degrading the function of other cellular components and activities. Unfortunately, aging causes loss of proteasomal function just as it degrades the function of all complex systems in the cell.
In today’s open access paper, researchers discuss the link between the age-related impairment of proteasomal function and the chronic inflammation that is characteristic of aging. This is a part of the increased attention given to the cGAS–STING pathway and its relevance in aged tissues. The sensor cGAS evolved to detect nucleic acids characteristic of invading pathogens, but is unfortunately also triggered by mislocalized DNA from the cell nucleus or mitochondria that escapes into the cytoplasm of the cell. cGAS in turn activates STING, a central inflammatory regulatory. Diminished proteasomal activity allows the build up of misfolded and other harmful proteins that can disrupt mitochondrial function and structure sufficiently to allow mitochondrial DNA into the cell cytosol.
This sort of connection is why interventions that improve forms of cell maintenance such as proteasomal activity and autophagy tend to reduce age-related inflammation. These forms of intervention range from exercise to sophisticated genetic upregulation or downregulation of specific protein machinery used in cell maintenance processes. Some are more practical than others, and effect sizes vary. What they all have in common is that they help to reduce the level of damage in the form of broken proteins inside cells, thereby improving mitochondrial function, and reducing cGAS-STING activity and consequent inflammatory signaling.
Impaired Proteasome as a Catalyst for cGAS-STING Activation in Alzheimer’s Disease
Misfolded proteins and protein degradation systems have contributed significantly to the understanding of Alzheimer’s disease (AD). The ubiquitin-proteasome system (UPS), is vital for clearing abnormal proteins that could trigger inflammation if accumulated. Neurons are particularly vulnerable to UPS impairment due to their high reliance on precise protein homeostasis for function and survival. Findings from the studies of the 5×FAD and tau-P301S mice revealed that the synaptic proteasome function is impaired even in the early stages, a phase before overt plaque formation, correlating with early memory deficits. Blocking proteasome function in healthy neurons causes AD-like effects, such as oxidative stress, synaptic loss, and cognitive decline.
Conversely, boosting UPS activity can reverse these effects. Deletion of a 26S proteasome subunit causes neurodegeneration and Lewy-like inclusions, accompanied by abnormal mitochondria, linking proteasome failure to mitochondrial dysfunction and neuronal damage that extends beyond protein aggregation. Increased production of reactive oxygen species (ROS) can damage mitochondrial lipids and proteins, compromise membrane integrity, and ultimately cause membrane rupture. This occurs due to abnormal protein aggregation caused by proteasomal failure, which disrupts redox balance. Although UPS is involved in mitochondrial quality control, its impairment weakens the removal of damaged mitochondrial proteins, leading to oxidative stress that eventually causes mitochondrial membrane collapse. This collapse can then leak mitochondrial DNA into the cytosol. This leaked mtDNA acts as a damage-associated molecular pattern, thereby activating the cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) DNA-sensing pathway, to cause neuroinflammation.
It has been shown in a neuron-specific proteasome knockout mouse that the cGAS-STING pathway was activated, as evidenced by increased protein levels of cGAS and STING, and pro-inflammatory factors, such as STAT1, NF-κB, IL-1β, TNF-α, and IL-6, as well as signs of neurodegeneration, including decreased brain weight and necroptosis markers. These results link proteasomal dysfunction to immune responses and cell death in the brain
