How To Stop Protein Misfolding (Proteopathy)

I tried folding protein once, but all I got was a ham and cheese sandwich (my attempt at telling a joke).

In this post we're discussing proteopathy, how proteins can cause chronic disease, and some strategies to prevent it all. 

Amino acids are just amino acids until they are folded improperly within the cell.

This misfolding is called proteopathy (also known as protein conformational disorder, or protein misfolding disease). R

Normally in healthy cells, misfolded proteins are either degraded or refolded correctly by chaperone proteins. R

Misfolded proteins can be toxic/damaging, carry out functions that destroy other cells or the body, which can be good in cancer, but dangerous in some chronic illnesses. 

It is one of the main pathologies of many neurodegenerative diseases, for example, misfolded proteins are what make amyloid beta plaques toxic in Alzheimer's (AD). R R

Once the proteins in AD are formed, it is quite challenging to unfold them, as the proteins are very stable. R R

^source from wikipedia

Chaperone proteins oversee the whole process in the ribosome and participate in every step in the handling of misfolded proteins, such as checking the quality, and if need be refold it in the correct way. R

They can also degrade the proteins if need be (via ubiquination or autophagy). R

There are two types of chaperones we need to address

1. Chaperones linked to protein synthesis (CLIPs) R

2. Heat shock proteins (HSPs) R

Hsp90 inhibitors typically activate HSF1, which in turn induces Hsp70:

• Hsp70 promotes their degradation via the UPS system R

• Hsp90 stabilizes client proteins and inhibits their ubiquitination R

To fix misfolded proteins, we either need to target production, regulate chaperone operation, induce protein degradation, enhance extracellular clearance, or counter proteotoxic stressors. 

Avoid:

Stressors (non exclusive list): R

• Aberrant physiological conditions (oxidation, osmolarity, pH)

• Alcohol, Nicotine

• Amino acid analogues (including from food sources - azetidine, canavanine)

• Anesthetics

• Anitiotics and anti-inflammatory drugs (puromycin, tetracylcine, NSAIDs, indomethacin)

• Emotional/psychological stress

• Environmental Stressors (heavy/transition metals, alcohols, aresenic, pesticides, mutagens, irritants)

• Hormonal imbalances (thyroid and growth hormone, IGF1)

• Nutrient intake/imbalances

• Pathophyiological states (fever, inflammaiton, infection, hypoxia, reperfusion)

• Physical stress (temperature, irradiation, UV, mechanical stress)

• Trauma, injury

Useful Supplements:

• Curcurmin R

• EGCG R

• Myricetin R

• Olive Leaf Extract R

• Oregano R

• Peppermint R

• Quercetin R

• Resveratrol R

• Rosemary R

• Sage R

• Thyme R

Useful Drugs:

• AADvac1 (Active tau based immunotherapy) R

• ACI-35 (Phospho-tau vaccine) R

• Arimoclomol (HSP activation) R

• Deferiprone (Iron chelator) R

• Istradefylline (Adenosine A2A receptor antagonist) R

• Nuedexta (NMDA receptor antagonist) R

• Rolipram (PDE4 inhibition) R

• TRx0237 (Tau aggregation inhibitor) R

Pathways To Target:

• BACE inhibition R

• cAMP activation R

• GSK3beta inhibition R

• HDAC inhibition R

• HSF1 activation R R

• Hsp70 activation R R

• Hsp90 inhibition R R

• Hsp104 or Hsp40 activation (high levels can degrade tau and A-beta) R R

• LXR-beta receptor agonists (induce Aβ into the extracellular space via ABCA1 transporter) R R

• p38 (MAPK) inhibition R

• PDE4 inhibition (such as with Rolipram) R

• mTOR inhibition (such as curcurmin and resveratrol) R

• Tau inhibition R

• ULK1 inhibition R

Genetics:

• Protein conformation

• Protein stability

• Subunit stoichiometry