When Good Proteins Go Bad: The Problem of Misfolding

Small protein molecules, practically invisible to the naked eye, could cause so many cognitive issues indeed.

We’ve spent quite a bit of time talking about inflammation and some of the signalling molecules involved in it, including cytokines.

But there’s something interesting hiding in that discussion, which is the fact that many of those cytokines are proteins.

Proteins are some of the most remarkable molecules in our bodies. A protein isn’t simply a string of amino acids floating around inside a cell. That chain needs to fold into a very specific three-dimensional structure before it can perform its intended function. In other words, the shape of a protein matters.

A protein with the right amino-acid sequence but the wrong three-dimensional structure may not function properly. Which brings us to a rather interesting question:

What happens when our proteins get their shape wrong?

Because occasionally, proteins don’t fold correctly. Sometimes, instead of being repaired or removed, these misfolded proteins can stick together and form aggregates.

That becomes particularly interesting when we look at what happens inside the brain.

But before we get there, let’s take a step back.

There are so many different types of proteins in the body. In fact, it is estimated that the human body contains 80,000–400,000 different types of proteins, and these proteins are present for different purposes in the body.

Now, the cells in our body can manufacture these proteins via the activity of specific genes within its deoxyribonucleic acid (DNA) identifier. These proteins are peptide polymers that contain multiple amino acids all fused together. “Peptides” refer to shorter chain/simpler amino acid polymers, while “proteins” refer to longer chain/more complex amino acid polymers.

Interestingly, while the production of the protein may not be problematic, it’s the retention of protein function that is key. A cat might happily play with a ball of yarn, batting it around and chasing it across the floor.

But if you take that same ball of yarn and completely unwind it into one long, straight string, the cat probably isn’t going to find quite as much joy in it.

The material hasn’t changed, but the shape has.

And proteins are somewhat similar.

The amino acids that constitute a protein may still be exactly the same. However, if the protein loses the three-dimensional structure that allows it to perform its function, it may no longer behave like the functional protein we started with.

The same basic idea applies to proteins inside our bodies.

Our blood, for instance, contains haemoglobin proteins that transport oxygen from our lungs to tissues throughout the body. We therefore need these haemoglobin molecules to retain the molecular structure and functional properties required to carry and release oxygen appropriately.

This is particularly relevant in diabetes, where persistently elevated blood glucose can cause glucose to react non-enzymatically with proteins in a process known as glycation. Haemoglobin (Hb) is one of the proteins affected by this process, which is why glycated Hb (also known as HbA1c) can be used as a marker of long-term blood glucose exposure.

Hb normally acts as a carrier for oxygen, picking up oxygen in our lungs and transporting it through the bloodstream to tissues throughout the body. However, glycation does more than simply attach glucose molecules to haemoglobin. It can also cause structural and conformational changes to the protein, including changes involving the heme groups that are responsible for oxygen binding. These structural changes can therefore affect the ability of haemoglobin to perform its normal oxygen-transport function.

So here we already have an example of something rather interesting:

The cell can successfully manufacture a protein, but that does not necessarily guarantee that the protein will remain perfectly functional throughout its lifetime.

And this brings us back to the question we started with:

What happens when a protein gets its shape wrong?

A protein’s amino-acid sequence provides the molecular information needed to determine its structure, but the final three-dimensional configuration depends on how the chain folds and interacts with its surroundings.

And that structure matters.

A protein with the correct amino-acid sequence but the wrong three-dimensional configuration may no longer be able to perform its intended function properly.

This is where protein folding becomes particularly important.

For example, the keratin proteins in our hair contain disulfide bonds that help stabilise the structure of the hair fibres. The arrangement of these bonds contributes to the shape of the hair, which is why chemical treatments such as perms can alter the shape of the hair by breaking and reforming these disulfide bonds.

When there is excess heat applied, or when the acidity/alkalinity of the protein’s surrounding environment is changed up, it will refold into its next most stable configuration. Under extreme circumstances, the protein will undergo denaturation and may end up changing its conformation permanently.

If we do look at what happens when we cook an egg white. A raw egg white is translucent and behaves more like a liquid, but a completely cooked egg white looks more like a white opaque solid. Is that a permanent denaturation though? Scientists suggest .

And interestingly, even the idea that denaturation must always be completely irreversible is not quite as straightforward as it might seem. Scientists have demonstrated experimental methods for refolding certain proteins from cooked egg white, showing that protein denaturation is not necessarily synonymous with permanent destruction of the protein’s molecular information.

The broader idea, however, remains important:

Proteins require the appropriate three-dimensional structures to perform their functions properly.

Fortunately, our cells have quality-control systems that continuously monitor and manage proteins that become damaged or misfolded. Molecular chaperones can help some proteins fold correctly, while other damaged or misfolded proteins can be targeted for degradation through systems such as the ubiquitin-proteasome pathway and autophagy.

In a healthy cell, this means that individual misfolded proteins do not necessarily have the opportunity to accumulate indefinitely.

But what happens when these quality-control systems cannot keep up?

This becomes particularly interesting when we look at the brain.

One of the defining pathological features of Alzheimer’s disease is the accumulation of abnormal protein assemblies, including extracellular amyloid plaques containing amyloid beta (Aβ) and intracellular neurofibrillary tangles composed primarily of abnormal tau protein.

But there is an important distinction here.

It isn’t necessarily the large plaques and tangles themselves that explain every aspect of the disease.

Increasing evidence suggests that smaller, soluble forms of Aβ and tau can also interfere with neuronal function and contribute to synaptic dysfunction. These abnormal protein species can interact with one another and participate in biochemical pathways that ultimately contribute to neuronal damage.

As these abnormal protein species accumulate and interfere with the normal operation of neurons, the consequences can extend to the synapses and other structures responsible for communication between brain cells.

And this gives us the first major problem with protein aggregation:

The wrong proteins, in the wrong place, can interfere with the normal machinery of the cell.

But there is another problem.

The accumulation of abnormal protein species can also interact with pathways involved in oxidative stress and inflammation. These inflammatory responses can further contribute to neuronal dysfunction and, when sufficiently prolonged or severe, neuronal injury and death.

Over time, the combined effects of protein aggregation, disrupted cellular processes, synaptic dysfunction, oxidative stress and neuroinflammation can contribute to the progressive loss of cognitive function associated with Alzheimer’s disease and other neurodegenerative disorders.

And suddenly, that rather simple question we started with: what happens when a protein gets its shape wrong? lands us in a more complex arena.

Because sometimes, a protein with the wrong shape isn’t simply a broken protein.

Sometimes, it can become part of an entirely different problem.

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