
The Classic Case of Misfolded Proteins
Did you know that misfolded proteins cause Mad Cow Disease? Strictly speaking, people don’t get Mad Cow Disease. Instead, cows do! Duh!
When people eat the meat of infected cows, then they get Creutzfeldt-Jakob Disease (CKD), a kind of dementia. CKD is bad news and kills you quickly. Probably the most common example of disease caused by misfolded protein is CKD.
Whether we’re talking cows or humans, misfolded proteins called prions cause the disease. Curiously, we don’t know the biological function of healthy prions. However, we do know that prions become misfolded when they’re infected. Misfolded prions spread by inducing misfolding in healthy prions, leading to a chain reaction.
Unfortunately, this causes a rapidly advancing infectious disease that results in degeneration in the brain. It’s tickets when your brain turns to mush.
Other Illnesses linked to Misfolded Proteins
We’ll discuss a number of other diseases caused by misfolded proteins in this post. Previously, I discussed the basic physiology of proteins and the importance of protein folding. Fortunately, that’s an easy to understand overview of the basic science and it’s a good idea to have a look at that discussion. Indeed, it’s fascinating stuff!
Small as they are, misfolded proteins have massive consequences for human health. Notwithstanding their minute size, they underpin some big diseases. In what follows, I’ll discuss various diseases that involve misfolded proteins:
- Parkinson’s Disease
- Alzheimer’s Disease
- Huntington’s Disease
- Amyotrophic Lateral Sclerosis
- Multiple System Atrophy
- Frontotemporal Dementia
- Chronic Traumatic Encephalopathy
- Spinal and Bulbar Muscular Atrophy
There are a few conditions that are obviously missing from this list, like Lewy Body Dementia and Limbic-predominant Age-related TDP-43 Encephalopathy. I might add them to this post at some point in the future.
Parkinson’s Disease
Cause of PD
We’ve discovered that misfolded proteins are a major cause of Parkinson’s Disease (PD). In particular, a misfolded protein called alpha-synuclein turns out to be the culprit in PD. That’s not to say this protein is the only cause of PD. There is no doubt that genetics and environmental exposure to toxins also play a role. However, the genetics increases susceptibility to protein misfolding. Likewise, neurotoxins like pesticides induce protein folding. So, one way of the other, we can’t get away from protein misfolding!
Some experts have a different view. They argue that other forms of intracellular pathology are also independent causes of PD. In that list, they would put:
- Mitochondrial dysfunction.
- Oxidative stress.
- Impaired protein clearance.
- Inflammation.
At least in my opinion, that’s not correct. I figure that these intracellular problems are not independent causes of PD. Instead, they arise as a direct result of protein misfolding.
Misfolded Alpha-Synuclein
Misfolded alpha-synuclein forms clumps within cells that disrupt cellular functions. We believe that this clumping process starts in the gut. Over the course of many years, blobs of misfolded alpha-synuclein gradually spread from the gut to the brain. These protein aggregates go by the name Lewy bodies. They impair nerve transmission by disrupting synapses, the connections between nerves.
In particular, Lewy bodies cause degeneration of dopaminergic neurons. This break down happens in the substantia nigra (“dark substance”) in the brain. The substantia nigra is important because it is the source of most of the dopamine in the brain. So, damage there leads to loss of dopamine in the brain. Dopamine is a major neurotransmitter in the brain. Low dopamine levels cause the characteristic motor symptoms of PD: tremor, slow movement, stiffness and instability.
Swollen Nerve Cells
You should be aware of an important knock on effect of the cellular damage in synapses. Surprisingly, this damage often goes unrecognised. It’s like our thinking stops when we get to the dopamine loss because it’s such a big deal. However, there is more to PD than just dopamine loss.
Importantly, Lewy body damage causes activation of immune cells in the brain. We call these immune cells microglia. In turn, microglial activation triggers widespread inflammation in the brain. This is a huge problem.
This inflammation significantly worsens the ongoing pathology in PD. For instance, lowering inflammation in PD brains, reduces symptoms. Likewise, controlling inflammation in PD improves dopamine levels!! Yet somehow, we often miss this critical point in the management of PD. It’s a lever we’re not using. (Talk to me about this.)

Misfolded Proteins in Alzheimer’s Disease
Misfolded beta-amyloid (Aβ) proteins are the primary pathology in Alzheimer’s Disease (AD). We have a good understanding of the role of Aβ in AD. Notwithstanding, the fact that Aβ is a misfolded protein often goes unmentioned.
Aβ peptides come in varying lengths. We measure the length in kilodaltons. There are two main forms of Aβ: Aβ40 and Aβ42. They are 40 and 42 kilodaltons long, respectively. The longer one, Aβ42, is more prone to misfolding due to its hydrophobic nature and tendency to self-associate. Say what?
Simply put, it means Aβ42 has a water-repelling stretch of amino acids at its C-terminal end. This hydrophobic region makes Aβ42 unstable in a watery environment, like the brain’s extracellular fluid. As a result, these peptides tend to clump together to reduce their exposure to water. Amazing, hey? We call these clumps amyloid plaques, a pathological hallmark of Alzheimer’s. Amyloid plaques are to AD, as Lewy bodies are to PD.
Like alpha-synuclein in PD, misfolded Aβ disrupts normal synaptic function in AD. The release of neurotransmitters and receptor functions become affected when this happens. In turn, that impacts on the brain’s ability to send nerve signals. Of course, this all compromises brain function.
Damage to Cellular Engines
Additionally, Aβ causes mitochondrial dysfunction. Mitochondria are critical for energy production in cells. They’re like the engines in cells. Not surprisingly, a faulty engine is a problem. Out bodies have some neat tricks. When mitochondria malfunction, the body sends signals telling it to commit suicide. It’s like scapping your car when the engine burns out. It’s not worth the repair. In cells, we call this suicideapoptosis, programmed cell death.

Additionally, Aβ causes oxidative stress through the production of reactive oxygen species (ROS), which damages lipids (fats), proteins, and DNA in neurons. This triggers a massive inflammatory response. It’s a major issue in Alzheimer’s.
Tangled Nerves
In addition to Aβ pathology, in AD, another protein called tau becomes hyperphosphorylated. This tau protein forms tangles inside neurons. We call these misfolded proteins neurofibrillary tangles. As the name implies, these are literally nerves that get into a knot.

There is a reticulation of tiny, delicate tubes inside neves. We call these microtubules. Microtubules are vital to nerve functioning because they transport nutrients. Knotted nerves bend these tiny tubes. Consequently, nutrients can no longer flow down the tubes. These nerves then starve and die off.
Huntington’s Disease
Changes deep inside the brain lead to Huntington’s Disease (HD). At the core of HD is a genetic mutation that misfolds a protein called huntingtin. Normally, it helps with cellular functions. Unfortunately, when misfolded, it becomes harmful.
Under normal circumstances, the transport of nutrients and other cellular cargo along microtubules depends on huntingtin. When huntingtin misfolds, it forms a shape that blocks the flow of nutrients. When that happens, intracellular transport goes for a loop. Consequently, delivery of nutrients, organelles, and synaptic vesicles stops. These are all crucial for nerve function and survival.
Just like happens in AD and PD, misfolded proteins clump together in the brain. This happens especially in areas like the basal ganglia, which control movement and coordination. The cortex, responsible for thinking and decision-making, takes a hit. These growing clumps of protein disrupt communication between brain cells and eventually cause these cells to die.
The loss of brain cells leads to the classic symptoms of HD: uncontrolled movements, mood changes, and difficulties with thinking. Over time, parts of the brain shrink, especially those critical for managing movement, thinking and emotions. Predictably, symptoms worsen as the disease progresses.
Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) causes damage to motor neurons in the brain and spinal cord. It leads to progressive muscle weakness and paralysis. The underlying pathology in ALS is, you guessed it (!), of clumps of misfolded proteins. There are two proteins that are the bad guys: TDP-43 and SOD1.
TAR DNA-binding protein 43 (TDP-43) is a protein that plays a key role in many cellular functions. These include RNA metabolism, mRNA transport, and microRNA maturation. Normally, TDP-43 lives in the cell nucleus. Except that in ALS, clumps of misfolded TDP-43 accumulate in the cytoplasm of cells, outside the nucleus. In a way, it’s just like a misbehaving child. We throw the naughty kid out of the house and tell him to go and play outside!
Interestingly, the TDP-43 bad guy plays a role in other types of dementia. Undoubtedly, you’ll notice the recurrent themes in this story of misfolded proteins. The same players come up again and again. Just like movie stars, they become quite typecast.
Superoxide dismutase 1 (SOD1) is an enzyme that normally protects cells from oxidative stress. However, when it becomes misfolded in ALS, it malfunctions. Without its protection, damage happens to nerves. So, there’s no question that misfolded proteins drive ALS.
Do you remember the South African rugby legend, Joost van der Westhuizen? Sadly, he died of ALS in 2017. It’s sobering to realise that misfolded proteins even take out the stars. To be sure, they are that bad!
Multiple System Atrophy and Misfolded Proteins
In Multiple System Atrophy (MSA) there is a build up of misfolded alpha-synuclein in glial cells. Yep, the same alpha-synuclein involved in Parkinson’s. This time, though, the Lewy bodies accumulate in glial cells, not synapses.
Glia, or glial cells, are structural support cells in the brain and are not actually nerve cells. The word glia means glue in Latin. Glia provide a scaffolding for nerves, literally gluing them together. What’s more, an important role of glial cells is the production of a fat that speeds up nerve conduction.
That fat, myelin, acts like an insulator. The “white matter” of the brain gets its colour from myelin, which is white. Cells with the delightful name of oligodendrocytes produce myelin. They hang out inside glial cells.
In 1989, Papp and Lantos were investigating some obscure neurological diseases. They noticed clumps of misfolded alpha-synuclein in the oligodendrocytes in these patients. Previously, we thought that striatonigral degeneration, olivopontocerebellar atrophy, and Shy-Drager syndrome were independent conditions. Based on their findings, Papp and Lantos realised that all three conditions were actually all manifestations of MSA. Of course, the common thread in these conditions is Lewy bodies in oligodendrocytes.
In MSA, the damage happens mainly in brain regions involved in movement. So, it looks like PD. Additionally, brain nuclei involved in autonomic functions find themselves caught up in the pathology. This effects the control of blood pressure, continence, digestion, breathing, temperature regulation and so on. That results in what we call autonomic dysregulation.
In recent years we have learnt that glial cells modulate cognitive functioning. MSA is a complex illness. It affects brain function at multiple levels. As always, inflammation makes everything worse.

Frontotemporal Dementia
Misfolded proteins are also characters in the story of Frontotemporal Dementia (FTD). In fact, they are the stars of the show. Specifically, misfolded tau clumps together in the nerves of these patients. In FTD, these aggregates have the name Pick bodies. They create neurofibrillary tangles. As occurs in AD, these knotted nerves bend microtubules. Just like you’d expect by now, those poor little neurons starve to death.
You can see the patterns. Pick bodies are to FTD as amyloid plaques are to AD, as Lewy bodies are to PD. Same tune, just a different key.
In FTD, TDP-43 is also one of the characters in the storyline. You met him when we were discussing ALS. Typecast, TDP-43 still takes on the bad guy role. Remember the naughty kid who had to go and play outside? Well, just like happens in ALS, in FTD TDP-43 relocates, moving from the cell nucleus to the cytoplasm. Those clumps of misfolded TDP-43 impair gene regulation, protein synthesis, and RNA metabolism. The kid just doesn’t know how to play nicely!
In the context of FTD, it’s worth mentioning fused in sarcoma (FUS). This is a rare feature of FTD but also involves misfolded proteins. Just like TDP-43, FUS is an RNA-binding protein that plays a role in gene regulation. Misfolding and aggregation of FUS disrupts RNA homeostasis and other cellular functions.
Overall, the net effect of tau misfolding, TDP-43 misfolding and occasional FUS misfolding causes progressive damage to the frontal and temporal lobes of the brain, affecting behavior and language and emotional functioning. FTD is serious. It accounts for many cases of dementia.
Chronic Traumatic Encephalopathy
Chronic Traumatic Encephalopathy (CTE) arises from repeated blows to the head that cause concussion. As might expected then, professional contact sport players are at particular risk of CTE. Boxing, MMA, football, rugby, ice-hockey and so on.
By now, you must be familiar with the tune. The hallmark of CTE is the pathological aggregation of misfolded tau protein into neurofibrillary tangles within neurons and astrocytes. We’ve repeatedly discussed the damage misfolded tau causes to microtubules and intracellular nutrient transport. Curiously, clumps of tau aggregate in the bottom of cortical sulci, the folds in the outer surface of the brain. It’s as if it is a sediment.

Notwithstanding tau’s role, other actors also feature on the CTE stage. Correspondingly, please welcome back the good old bad guy, TDP-43. Without a doubt, we know that in severe cases of CTE there is involvement of TDP-43. Also, we see an overlap with conditions like ALS and FTD.
Spinal and Bulbar Muscular Atrophy
Spinal and Bulbar Muscular Atrophy (SBMA) is a rare genetic disorder involving the X chromosome. As you’d expect from our script, misfolded proteins clump together. Also known as Kennedy’s Disease, it mainly affects men.
In SBMA, the problem lies with a protein called the androgen receptor, which helps process hormones like testosterone. Due to a genetic error, this protein doesn’t work properly. Clumps of misfolded proteins that form in the spinal cord and brainstem affect movement. Over time, these nerve cells become damaged and die, leading to muscle weakness.
Symptoms of SBMA often appear in adulthood, typically between 30 and 50 years of age. People may notice difficulty swallowing, speaking, or holding their head up, as well as weakness in the arms and legs. In some cases, hormonal changes can cause additional symptoms like breast enlargement or reduced fertility in men.
Misfolded Proteins: Implications
In conclusion, every single condition we’ve discussed features misfolded proteins. Proteostasis is faulty in every disease. Furthermore, in every case, misfolding of proteins leads to neuronal death and serious neurological disease. As one would expect, neuroinflammation accompanies all of these diseases. The inflammation is serious and substantially worsens the symptoms.

Make no mistake, these are incurable diseases. We could nonetheless make a positive difference if we targetted inflammation. Doing so would help to reduce the severity of symptoms and would improve quality of life.
There is hope. Lifestyle change is critical to the big picture. It can bring about incredible gains. Think beyond the drugs. You need them, but there is more you can do! And never give up.
