Many proteins can form transient aggregates, in which misfolding or chemical decoration allows solid clumps of protein to precipitate from solution and disrupt cellular biochemistry. A much smaller number of proteins can form persistent aggregates, however, and this unfortunate mechanism is an important contributing cause of a variety of age-related conditions. This is particularly the case in the brain. Consider amyloid-β, tau, and α-synuclein, for example, contributing to Alzheimer's, Parkinson's, and other neurodegenerative conditions. Meanwhile in the rest of the body, transthyretin amyloid is likely important in heart failure, while a number of other types of amyloid (such as medin) likely contribute to aging in more subtle ways.
Our biochemistry is capable of clearing protein aggregates via a form of autophagy called aggrephagy. Autophagy is the name given to a collection of processes that identify and flag unwanted molecules and structures, and in a variety of ways deliver those flagged molecules and structures into a lysosome. Once inside a lysosome, enzymes break down the material for recycling. Clearly the normal operation of aggrephagy is not sufficient to the task of keeping persistent aggregates from accumulating to cause disease, but it does have an impact. Thus the research community is interested in finding ways to meaningfully enhance the operation of aggrephagy. That in turn requires a better understanding of how exactly aggrephagy functions.
Your cells break down protein clumps to smaller pieces before taking it to the trash
A new study shows that our cells' ability to clean out old protein clumps, known as aggregates, also includes a previously unknown partnership with an engine that breaks down bigger pieces into smaller before "taking it to the trash." The process involves something called the proteasomal 19S subunit and DNAJB6-HSP70-HSP110 chaperone module, which together practically form a grinder. This is a very important key that may lead to better treatments of diseases like characterized Alzheimer's, Parkinson's, Huntington's, ALS, and other diseases that are characterized by the accumulation of clumps, in most cases formed by a specific protein
"We know that augmenting autophagy, which is one of the two major cleaning systems in our cells, can delay the onset of several of the devastating neurodegenerative diseases mentioned. Our findings suggest that a combined treatment where we enhance both the breaking down of the big protein clumps into smaller pieces to make them a better substrate for autophagy and autophagy, may be a much better therapeutic approach for these diseases. We are just starting to decipher the mechanism of this whole cell-cleaning process, and we need to deep dive into the details before we can start to work on actual treatments, but understanding how we can enhance it, will certainly help to eliminate, at least partially, those toxic protein aggregates leading to the above-mentioned lethal neurodegenerative diseases."
A chaperone-proteasome-based fragmentation machinery is essential for aggrephagy
Perturbations in protein quality control lead to the accumulation of misfolded proteins and protein aggregates, which can compromise health and lifespan. One key mechanism eliminating protein aggregates is aggrephagy, a selective type of autophagy. Here we reveal that fragmentation is required before autophagic clearance of various types of amorphous aggregates. This fragmentation requires both the 19S proteasomal regulatory particle and the DNAJB6-HSP70-HSP110 chaperone module. These two players are also essential for aggregate compaction that leads to the clustering of the selective autophagy receptors, which initiates the autophagic removal of the aggregates. We also found that the same players delay the formation of disease-associated huntingtin inclusions. This study assigns a novel function to the 19S regulatory particle and the DNAJB6-HSP70-HSP110 module, and uncovers that aggrephagy entails a piecemeal process, with relevance for proteinopathies.
View the full article at FightAging
