Category: Dementia

Protein Waste Management in Neurodegenerative Diseases and Sleep

When I was in graduate school for molecular biology, one of the labs in my department studied chaperones, which are protein enzymes that assist in the folding of proteins into their functional, three-dimensional shapes. That lab (Dr. Jeff Brodsky was the Principal Investigator/P.I.) used the simplest eukaryotic cell model system, Saccharomyces cerevisiae (a.k.a. baker’s yeast), to study chaperones. I secretly thought to myself, “who cares” and “why would anyone get excited about studying that?”

But now I feel a little silly that I thought those disparaging things about what the Brodsky lab studied/studies because, as it turns out, protein misfolding and aggregation is a common characteristic of neurodegenerative diseases. The problem is that these aggregates of proteins do not get degraded like most misfolded proteins, nor do they get cleaned up and washed away in the cerebral spinal fluid (CSF) through the glymphatic system during sleep. Thus, these aggregates end up causing the neurons and glial cells to kill themselves (called apoptosis).

Neurodegenerative Diseases and their Associated Misfolded and Aggregated Proteins

The Brodsky lab studied chaperones in yeast, but sometimes they’d also try to bring human health relevance to their research, and when they did that they would study the protein that is misfolded in cystic fibrosis – CFTR (Cystic Fibrosis Transmembrane conductance Regulator). The reason I bring up CFTR in a post about neurodegeneration is to contrast what happens in lung cells (ionocytes) that express the misfolded CFTR protein to what happens in brain cells expressing the proteins that are involved in neurodegenerative diseases. The bottom line is that the cystic fibrosis lung cells do not end up killing themselves like the neurodegenerative brain cells do, despite the unfolded protein response (UPR) being activated in both cell types/conditions, which typically initiates programmed cell death (apoptosis).

One thing to keep in mind when comparing lung and brain diseases is that there are many different types of lung diseases that have many different types of mechanisms, but nearly all brain-related diseases (with the exception of brain cancers, for the most part) appear to have the same type of mechanism: protein misfolding, aggregation, and lack of clearing the aggregates, which leads to cell death. What this means is that brain cells (neurons and glia) are particularly sensitive to protein aggregates – these aggregates must be cleaned up ASAP or else the cells will kill themselves, leaving extracellular aggregates (sometimes the aggregates are secreted by the cell instead of killing itself, too), which can also inhibit neuronal signaling.

So how do we get rid of these protein aggregates? Well, usually, they are washed out of the interstitium (the extracellular space between cells in the brain) with the cerebral spinal fluid (CSF) while we are asleep. In fact, researchers suggest that this “waste management” is the primary function of sleep – to get rid of unnecessary proteins that were made during the day through proteolysis and clearing via the CSF and the glymphatic system, the recently discovered macroscopic waste clearance system through parivascular tunnels in the brain (created by astrocytes/astroglia). Furthermore, these protein aggregates can also trigger inflammation, which causes multiple brain toxicities.

When we do not sleep very much or very deeply, the brain does not get enough time to wash away its waste products, thus causing their accumulation and degenerative effects. Thus, there is a higher risk of developing dementia in people who have poor sleep habits. Therefore, sleep is not just for your beauty or comfort – it’s important for your brain function which means it’s vital for life. Lack of sleep kills.

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