The Awesome Complexity & Astonishing Beauty of Proteostasis

Misguided & Misguiding: Misfolded Proteins

Proteostasis is the system our bodies use to keep proteins in functional balance. Normally, it works brilliantly. However, misfolded proteins arise when proteostasis goes wrong. This is more likely to happen the older you get. Now, you might think that misfolded proteins are not a big deal but you’d be dead wrong! As it so happens, misfolded proteins create major problems. In fact, these little bent structures are the cause of many serious diseases. For example, Parkinson’s disease and amyotrophic lateral sclerosis.

Just as a single musician playing out of key can ruin the entire symphony, so tiny misfolded proteins can cause chaos in the body and brain. As a result, it’s appropriate to take misfolded proteins seriously. To that end, this post is mainly intended for people with brain-related illnesses and their caregivers.

In essence, this post is a primer for two (or more) posts that are still to come. It provides the relevant background concerning proteins. You’ll learn how misfolded proteins arise and how your body should deal with them. In a later post, I’ll chat about the different brain diseases caused by misfolded proteins. I want to get across how chronic neuroinflammation adds to the burden. In a subsequent post, I’ll also discuss things you can do to deal with inflammation. In fact, treatment is a huge topic and we can’t deal with it all in a few posts. Still, I’ll point you in the right direction.

The discussion gets a little technical here and there but you don’t need any medical or biological knowledge to understand. I assume you’re smart. Just concentrate and think about what I’m saying. It will help you understand your illness. It’s easier to deal with disease when you know what’s going on. Okay, are you ready?

The Wonder of Proteostasis

First, we need context. Let’s start with normal physiology. You probably know that proteins are biological building blocks. They’re the topic of discussion. Our bodies use a beautiful, finely tuned process to maintain protein homeostasis and ensure that our proteins are all working properly. As mentioned above, we call this process proteostasis. Isn’t that a lovely word? It was coined in a 2008 paper, so the term is fairly new. Interestingly, it was first used in a discussion about treating disease by intervening at the level of protein homeostasis.

Proteostasis describes the regulation of the protein life cycle. That includes protein synthesis, folding, trafficking, and degradation. In short, you gotta make the proteins, bend them into the right shape, send ’em to the right place to do their work, and break them down when they stop working. Obvious, right?

The proteome refers to the protein contents of a cell, of an organ, and, hey, even of you! Like a symphony (I like this analogy 😂), the proteome is a complex in-tune system. So, proteostasis is like the conductor, ensuring that everyone plays in tune and in rhythm. Consequently, proteostasis crafts a harmonious proteome. Beautiful, isn’t it?

Molecular Chaperones

Now, it’s fascinating that proteostasis includes what we call “molecular chaperones.” These are specific heat shock proteins, with thrilling names like Hsp70 and Hsp90, that guide protein folding. During protein synthesis, they shape proteins according to plan. A nip and a tuck to make sure the shape is just right.

Additionally, the chaperones refold partially misfolded proteins. Like any good chaperone, they also prevent the proteins from getting too close and groping each other. If they don’t, the proteins form a clump, what we call an aggregate. For example, Hsp70 prevents aggregation by sequestering exposed hydrophobic regions on misfolded proteins. It turns out that stopping protein groping is really important. Like, no orgies!

Protein Mince Machines

Did you know that our bodies have built in protein mince machines? In particular, these take the form of barrel shaped proteins called proteosomes. Severely misfolded proteins are beyond hope. When that happens, the chaperones tag them as mutants. To do that, they attach a little flag of ubiquitin to the misshapen protein. Tagged misfolded proteins then go into a proteosome barrel where enzymes chop them up. Thereafter, the leftovers drift back into the cytoplasm for recycling. It’s all very neat and efficient.

Why is Protein Folding Important?

Notably, proteins are a perfect example of the synergy between form and function. The physical 3D structure of a protein determines its function. Therefore, to function correctly, a protein must take the correct 3D shape. Proteins comprise strings of amino acids. Consequently, a highly specific sequence of amino acids creates the correct protein shape. Proteins take many different shapes, as you can see below.

Proteins have a highly organized structure. We can think about this at different levels of abstraction. The crucial aspects of protein folding happens at the tertiary level of protein structure. The structural levels of a protein are as follows:

• Primary structure: This is a linear sequence of amino acids in a polypeptide chain.
• Secondary structure: This defines local folding patterns. Typically, this includes alpha-helices or beta-pleated sheets stabilized by hydrogen bonds.
• Tertiary structure: This is the overall 3D folding of a single polypeptide chain. Interactions like hydrogen bonds, disulfide bridges, hydrophobic interactions, and ionic bonds determine the shape. This is what defines the function of the protein.
• Quaternary structure: Some proteins consist of more than one polypeptide chain. The arrangement of these chains forms this level of structure. An example of such a protein is haemoglobin.

Proteostasis: Conclusion

We haven’t discussed every aspect of proteostasis, which is fine. In terms of neurological disease, it’s the information about misfolded proteins that is important. We’ll deal with different diseases caused by misfolded proteins in a subsequent post. A further post will cover what you can do about these problems. If you’d like more information, a summary of proteostasis follows.

Appendix: Key Components of Proteostasis

1. Protein Synthesis
   • The code for a protein is in DNA.
   • Ribosomes translate the code using messenger RNA (mRNA) into proteins.
   • Proper protein folding begins during synthesis.
2. Protein Folding
   • Molecular Chaperones:
     • Assist emerging or stress-damaged proteins to fold into their correct shape.
     • Chaperones include heat shock proteins (HSPs) like Hsp70, Hsp90, and chaperonins like GroEL.
   • Chaperones prevent aggregation (clumping).
   • They sequester misfolded half-formed proteins.
3. Protein Trafficking
   • This concerns the transport of proteins to specific cellular locations (e.g., membrane, mitochondria).
   • Errors during trafficking can cause disease (e.g., cystic fibrosis).
4. Protein Quality Control
   • This is a critical part of proteostasis!
   • Proteostasis detects misfolded or damaged proteins. The solution is to refold or degrade.
   • The first solution is the “unfolded protein response.” Accumulation of misfolded proteins in the endoplasmic reticulum activates this system.
   • The other system is the heat shock response. It induces chaperones to act under stress conditions.
5. Protein Degradation
   • The ubiquitin-proteasome system targets misfolded or damaged proteins for degradation. Ubiquitin tags identify these damaged goods. The protein mince machine, the proteasome then dismantles tagged proteins into peptides.
   • Alternatively, autophagy breaks down proteins. This system removes aggregated proteins or organelles. Firstly, autophagosomes “swallow” (encapsulate) the misfolded protein. Like Pacman! Secondly, the debris is then delivered to lysosomes. Thirdly, lysosomes, which contain digestive enzymes, munch the protein residue. Yum yum!