Quick overview of what you’ll learn from this blog post:
- What is loss of proteostasis?
- Why does proteostasis happen?
- What are the consequences of proteostasis?
The Hallmarks of Aging describes the loss of proteostasis as the failure of our protein production machinery and is one of the reasons we age.
Proteins are involved in almost everything
Not everything that happens in our body is directly due to proteins, but almost everything is regulated by them. So even if proteins are not always directly involved in getting things done, they are indirectly responsible by acting as catalysts.
Proteins are the real workhorses of the cell and deal with a diverse range of tasks such as copying our DNA during replication, converting starch into sugar, and regulating the function, and structure of our tissues and organs.
Proteins are made up of hundreds, sometimes even thousands of smaller parts called amino acids that are linked together in long chains. There are a total of 20 amino acids that can be combined in many different ways to create a protein. These amino acids are:
- Alanine
- Arginine
- Asparagine
- Aspartic Acid
- Cysteine
- Glutamic acid
- Glutamine
- Glycine
- Histidine
- Isoleucine
- Leucine
- Lysine
- Methionine
- Phenylalanine
- Proline
- Serine
- Threonine
- Tryptophan
- Tyrosine
- Valine
- Selenocysteine
- Pyrrolysine
The proteostasis network
Our bodies rely on a flow of stable, correctly folded, and appropriate proteins in order to remain healthy. This healthy balance of protein production is known as proteostasis and is maintained by a system known as the proteostasis network, itself made mainly of proteins.
The parts of the proteostasis network are as follows:
| Ribosomes | Translates ribonucleic acid (RNA) into proteins. RNA is an important molecule in our cells that is used to construct other proteins. |
| Chaperones | Chaperones are a group of proteins that assist in protein folding by guiding the target protein to the correct form. |
| Proteasome | Protein complexes which degrade unneeded or damaged proteins marked by ubiquitin for destruction. |
| Lysosomes | Sacks of digestive enzymes within a membrane that can engulf and break down unwanted proteins and recycle them back into their base amino acids to be used to make new proteins. |
| Ubiquitin | A medium-sized polypeptide that can be attached to any protein to mark it for regulatory action. Ubiquitins can be used to mark unwanted proteins for recycling by the proteasome. |
How proteins are made
The proteostasis network starts off with a ribosome which translates a messenger RNA sequence into a protein. The sequence determines what order the amino acids are placed in the chain, the primary structure of the protein.
As the chain is constructed, it naturally twists and folds to form secondary structures. This shape is somewhat determined by the amino acids on the chain interacting. The most common secondary structures that chains form are known as α-helixes, β-sheets and turns.
As these secondary structures form, they too interact with each other just like the amino acids on the chains do. This causes the formation of three-dimensional folds and is considered the tertiary structure.
Lastly, this tertiary structure can function alone or it can join with others to form a greater quaternary structure.
What could possibly go wrong with all this machinery?
As you have probably gathered, the creation of proteins is a complex process and without a doubt, one where a lot can go wrong. Normally our proteostasis network does a great job of making sure that broken and unwanted proteins are fished out and disposed of and the correct proteins are produced.
But, as with many things, the aging process throws a spanner in the works of our protein making machinery. As the proteostasis network starts to fail this can lead to too few proteins, too many proteins, and misfolded proteins.
The most common issue that aging leads to is the build up of misfolded proteins. These bent misshapen proteins end up gathering in clumps known as aggregations. The accumulation of misfolded proteins associated with disease such as Alzheimer’s, Parkinson’s, and Amyotrophic lateral sclerosis.
But how do these misfolded proteins end up aggregating and causing problems in the first place?
- Environmental stress
- DNA mutations and translation errors
- The loss of chaperones
- The failure of degradation machinery
- Increasing aggregation
Environmental stress can lead to misfolded proteins. Changes such as a rise or fall of pH or oxidation levels can cause proteins to bond with other types of proteins which under normal conditions they would not do. Extremes of heat or cold can also disrupt the interactions between the amino acids in chains which causes the protein structure to lose shape.
DNA mutations and translation errors can also create misfolded proteins. Both of these things can lead to RNA that codes the incorrect amino acid. A similar situation can occur even if the RNA is correct, but the wrong amino acid gets added to the chain. If the incorrectly added amino acid is important for protein structure this can lead to the protein being structurally weak. Conditions such as cystic fibrosis are due to a mutation that makes mucus secretions thicken and build up in the lungs and digestive system.
The loss of chaperones, proteins that assist in protein folding, can also be a problem. It can happen due to a failure to transcribe DNA correctly, or due to the chaperones becoming trapped in protein aggregations. Trapped chaperones are associated with conditions such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis.
The failure of degradation machinery such as the proteasome and lysosome can also lead to an accumulation of misfolded proteins. Aggregations can also make the problem worse as they protect proteins within from being broken down and recycled. Trapped chaperones can also amplify this problem as it can prevent proteins from moving to where they can be processed by the proteasome.
Increasing aggregation. Finally, once aggregations start to build up, other proteins that would otherwise have been broken down can become attached to the aggregation. This leads to a vicious circle where more and more proteins join the aggregated mass. The prion protein is a prime example of this and a change to its structure is the basis for Mad Cow disease, a deadly neurological disorder that destroys the brain and spinal cord over time and can jump species.
What can we do about loss of proteostasis?
Researchers are working on drugs that can potentially address the accumulation of misfolded proteins but practices such as fasting and caloric restriction may also boost autophagy which may help.
- Find ways to improve degradation systems such as autophagy boosters
- Block, remove, or slow the creation of misfolded proteins using drugs
If researchers successfully find ways to slow down the accumulation of misfolded proteins or their disposal, it could mean that diseases such as Parkinson’s and Alzheimer’s could have a solution.