How To Stop Protein Misfolding (Proteopathy)

Proteopathies In Chronic Illness

 
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3175247/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3175247/

 

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. 

Contents:

  1. Basics
  2. Associated Diseases From Misfolded Proteins
  3. Chaperone Proteins
  4. What To Do About Misfolded Proteins

Basics

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

Associated Diseases From Misfolded Proteins

Proteopathy Major aggregating protein
Alzheimer's diseaseR Amyloid β peptide (AB); Tau protein
Cerebral β-amyloid angiopathyR Amyloid β peptide (Aβ)
Retinal ganglion cell degeneration in glaucomaR Amyloid β peptide (Aβ)
Prion diseases (multiple)R Prion protein
Parkinson's disease and other synucleinopathies (multiple)R α-Synuclein
Tauopathies (multiple)R Microtubule-associated protein tau (Tau protein)
Frontotemporal lobar degeneration (FTLD) (Ubi+, Tau-)R TDP-43
FTLD–FUSR Fused in sarcoma (FUS) protein
Amyotrophic lateral sclerosis (ALS)R Superoxide dismutase, TDP-43, FUS, C9ORF72, ubiquilin-2 (UBQLN2)
Huntington's disease and other trinucleotide repeat disorders (multiple)RR Proteins with tandem glutamine expansions
Familial British dementiaR ABri
Familial Danish dementia R ADan
Hereditary cerebral hemorrhage with (Icelandic) (HCHWA-I)R Cystatin C
CADASILR Notch3
Alexander diseaseR Glial fibrillary acidic protein (GFAP)
SeipinopathiesR Seipin
Familial amyloidotic neuropathy, Senile systemic amyloidosis TransthyretinR
Serpinopathies (multiple)R Serpins
AL (light chain) amyloidosis (primary systemic amyloidosis) Monoclonal immunoglobulinlight chainsR
AH (heavy chain)amyloidosis Immunoglobulin heavy chainsR
AA (secondary) amyloidosis Amyloid A proteinR
Type II diabetes R Islet amyloid polypeptide(IAPP; amylin)
Aortic medial amyloidosis Medin (lactadherin)R
ApoAI amyloidosis Apolipoprotein AIR
ApoAII amyloidosis Apolipoprotein AIIR
ApoAIV amyloidosis Apolipoprotein AIVR
Familial amyloidosis of the Finnish type (FAF) GelsolinR
Lysozyme amyloidosis LysozymeR
Fibrinogen amyloidosis FibrinogenR
Dialysis amyloidosis Beta-2 microglobulinR
Inclusion body myositis/myopathyR Amyloid β peptide (Aβ)
CataractsR Crystallins
Retinitis pigmentosa with rhodopsin mutations R rhodopsin
Medullary thyroid carcinoma CalcitoninR
Cardiac atrial amyloidosis Atrial natriuretic factorR
Pituitary prolactinoma ProlactinR
Hereditary lattice corneal dystrophy KeratoepithelinR
Cutaneous lichen amyloidosis R Keratins
Mallory bodies R Keratin intermediate filament proteins
Corneal lactoferrin amyloidosis Lactoferrin R
Pulmonary alveolar proteinosis Surfactant protein C (SP-C)R
Odontogenic (Pindborg) tumor amyloid Odontogenic ameloblast-associated proteinR
Seminal vesicle amyloid Semenogelin IR
Apolipoprotein C2 amyloidosis Apolipoprotein C2 (ApoC2)R
Apolipoprotein C3 amyloidosis Apolipoprotein C3(ApoC3)R
Lect2 amyloidosis Leukocyte chemotactic factor-2 (Lect2)R
Insulin amyloidosis InsulinR
Galectin-7 amyloidosis (primary localized cutaneous amyloidosis) Galectin-7 (Gal7)R
Corneodesmosin amyloidosis CorneodesmosinR
Enfuvirtide amyloidosisR EnfuvirtideR
Cystic Fibrosis R cystic fibrosis transmembrane conductance regulator (CFTR) protein
Sickle cell diseaseR Hemoglobin

^source from wikipedia

Chaperone Proteins

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

What To Do About Misfolded Proteins

 
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3402352/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3402352/

 

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:

 
 

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