Current Research and Therapeutics for Misfolded Proteins

Can we attribute intentionality to inflammation? Perhaps it was originally well-intentioned, the good kid trying to help. But then, it seems, it got in with the wrong crowd and it began to cause trouble. The good kid gone bad!

So, how do we fix inflammation in neurological diseases? Let’s briefly recap. To clarify, we have learnt about the miracle of proteostasis. Specifically, the way we synthesie, shape, maintain, and recycle proteins. That’s out body’s way of maintaining the integrity of all our proteins. Unfortunately, as we age, our capacity to maintain proteostasis deteriorates. Additionally, we get exposed to substances like pesticides that compromise proteins. Moreover, errors start to creep in. During protein synthesis, proteins get misfolded. Consequently, their functionality is seriously undermined. That’s when we get ill.

Often, the effect of misfolded proteins takes years to emerge. Nonetheless, the resultant illness can be devastating. We end up with conditions like Alzheimer’s or Parkinson’s disease. Notably, we can mitigate the effects of neurodegenerative diseases. In particular, we need to promote the clearance of toxic protein aggregates and reducing associated neuroinflammation. Truly, that’s the trick!

Reducing Protein Production

This is “the throwing the baby out with the bathwater” option. We nuke the bad guys but also might nuke the good guys. The prime exemplar is gene silencing therapy using antisense oligonucleotides (ASOs) to target mutant huntingtin in Huntington’s disease. A concern is the potential unintended effect on the wild-type (healthy) huntingtin gene. Although ASOs are designed to target the mutant gene specifically, there is a risk of also silencing the healthy, normal version of the gene to some degree. Huntingtin plays an important role in neuronal function, and reducing healthy huntingtin could cause neurological damage.

Animal studies and early human studies in early-stage Huntington’s patients showed that the reduction in the huntingtin gene correlated with improvements in some biomarkers. However, larger studies into safety and efficacy in human patients did not demonstrate significant clinical benefit in terms of motor function or disease progression. However, longer follow-ups are ongoing.

In other words, to date, reducing protein production has not proved to be a successful treatment for misfolded proteins.

Enhancing Protein Clearance to Reduce Misfolded Proteins

Passive Immunotherapy

Intense research led to the development of using monoclonal antibodies (aducanumab and lecanemab) help clear misfolded Aβ in Alheimer’s patients. Those two drugs are now FDA registered. Three people died during the drug trials. Their death were attributed to the drugs. The drugs cause micro-haemorrhaging and swelling in the brain. Aside from these horrendous side effects, they are so prohibitively expensive that only the super-rich can afford them.

Active Immunotherapy

Vaccines to stimulate immune responses against misfolded proteins are an option. A vaccine for use in Parkinson’s disease (PD) and multiple system atrophy (MSA) is being developed and early trials show very encouraging results. The drug does not even have a name yet, and goes by the moniker of UB-312. Its mechanism of action is to induce antibodies that bind to alpha-synuclein.

In animal models of PD, immunisation with UB-312 reduced the accumulation of alpha-synuclein in the brain and in the gut and prevented a decline in motor function. In a phase 1 trial of 20 human PD patients, they developed antibodies to alpha-synuclein within eight weeks of vaccination. The clinical benefits in humans have yet to be clearly delineated, but the presence of antibodies implies the likelihood of reduced levels of alpha-synuclein. At this stage, researchers are still investigating safety but so far it looks promising.

This information was presented in late 2024 International Congress of Parkinson’s Disease and Movement Disorders that concluded a few days ago. I want to stress that these are very early findings and we are a long way from having anything ready for clinical use.

Chaperone-based Strategies:

Small molecules like arimoclomol enhance molecular chaperones (Hsp70, Hsp90), improving refolding or promoting clearance via autophagy.

Modulating Autophagy and Proteasome Pathways

We could try boosting cellular clearance mechanisms. For instance, we could use mTOR inhibitors like rapamycin to enhance autophagy. That could increase lysosomal degradation of misfolded proteins. We could try proteasome enhancers. These are great ideas but are largely only theoretical at this point and more research needs to be done.

Stabilizing Protein Structures

We could use small molecules as chemical chaperones to stabilize native protein conformations and reduce misfolding. For instance, 4-phenylbutyrate (PBA) is a naturally occurring fatty acid derivative that has a number of potential therapeutic uses. For example, PBA can reduce the load of mutant or mislocated proteins in the endoplasmic reticulum (ER) in cystic fibrosis.

However, I’m only aware of animal research with PBA in the group of brain diseases we’re discussing here. There is a human trial underway currently looking at Parkinson’s patients but we await those results.

Addressing Mitochondrial Dysfunction from Misfolded Proteins

Reduce Oxidative Stress

Cells with nuclei in blue, mitochondria in green, and the actin cytoskeleton in red.
Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Misfolded proteins often accumulate in mitochondria, impairing their function and leading to oxidative stress and energy deficits. We could use antioxidants, of which there are some great natural alternatives. Likewise, we could use PPAR-gamma coactivator 1-alpha (PGC-1α) activators to boost mitochondrial biogenesis. Hah! Now that’s an interesting option. You’ll have to talk to me and I’ll explain.

Reducing Neuroinflammation from Misfolded Proteins

Misfolded proteins often activate microglia and astrocytes, leading to chronic inflammation and neuronal damage. To reduce inflammatiion you could try standard anti-inflammatory drugs (NSAIDs, colchicine) but these are associated with mixed results in neurodegenerative diseases.
Better still, you could use some of the wonderful specialised proresolving mediators we supply. Those amazing supplements flip a biochemical switch that stops inflammation.

Dietary Approaches to Misfolded Proteins & Restoring Proteostasis

Ketogenic Diet

A ketogenic diet shifts metabolism from glucose to ketones, reducing oxidative stress and improving mitochondrial function. Evidence suggests benefits in Alzheimer’s and Parkinson’s disease by enhancing autophagy and reducing inflammation.

Misfolded Proteins & Fasting

Fasting and caloric restriction promotes autophagy, which helps to clear misfolded proteins. Also, fasting reduces inflammatory cytokines, enhancing cellular resilience.

Polyphenol-rich Diet

Foods rich in polyphenols (e.g., green tea, berries, turmeric) possess anti-inflammatory, antioxidant, and autophagy-boosting properties. For example, epigallocatechin gallate (EGCG) in green tea modulates protein folding.

Omega-3 Fatty Acids

Found in fish oil, omega-3s are anti-inflammatory and support neuronal membrane integrity. These properties may reduce susceptibility to protein aggregation.

Supplements to Reduce Misfolded Proteins

Lastly, nutraceuticals that enhance proteostasis include:

  • Curcumin: Reduces beta-amyloid aggregation and inflammation.
  • Sulforaphane: Upregulates antioxidant and chaperone systems.
  • Vitamin D. An immune modulator that reduces neuroinflammation.

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