The Sciences
Unfolded/Misfolded Proteins -
These Make Us Age
Misfolded proteins are proteins that fail to fold into their correct three-dimensional structures, which is essential for proper function. Protein folding is guided by molecular interactions, but errors can occur (and they will) due to genetic mutations, environmental stress, or cellular dysfunction. Misfolded proteins can aggregate into insoluble clumps, altering cellular functions (gain of toxin) and eventually leading to unwanted cell death (loss of function). Both alternation and loss of cellular function are the key causes of degenerative diseases and aging.
Diseases Caused by Misfolded Proteins
Diseases caused by misfolded proteins include Alzheimer’s, Parkinson’s, Type 2 diabetes, and Huntington’s. The cell has quality control mechanisms, like chaperones and the ubiquitin-proteasome system, to detect and degrade misfolded proteins. However, when these systems fail, toxic accumulations can result in Endoplasmic Reticulum (ER) Stress, leading to cell damage and disease progression.
Endoplasmic Reticulum (ER) Stress
Endoplasmic reticulum (ER) stress occurs when the ER, responsible for protein folding and processing, becomes overwhelmed by misfolded proteins. This triggers the unfolded protein response (UPR) to restore balance by halting protein synthesis, enhancing protein folding, or degrading misfolded proteins. Prolonged ER stress leads to cell dysfunction or death.
Endoplasmic Reticulum- associated Degradation (ERAD)
ER-associated degradation (ERAD) is a cellular quality control mechanism that removes misfolded or damaged proteins from the endoplasmic reticulum (ER). It involves recognizing misfolded proteins, retrotranslocating them from the ER to the cytosol, and tagging them with ubiquitin for degradation by the proteasome. ERAD helps maintain protein homeostasis and prevents the accumulation of toxic protein aggregates. Dysfunction in ERAD is implicated in diseases like neurodegeneration, diabetes, and certain genetic disorders due to impaired protein clearance.
The structure of p97, an essential ATPase for ERAD
Type 2 Diabetes
Type 2 diabetes (T2D) is closely linked to the accumulation of misfolded proteins, particularly in pancreatic beta cells. These cells produce insulin, a hormone essential for glucose regulation. Insulin synthesis involves complex protein folding in the endoplasmic reticulum (ER). Misfolded proinsulin (precursor of insulin) places stress on beta cells, overwhelming their protein-folding capacity and causing ER stress.
If the stress is unresolved, prolonged ER Stress can lead to beta-cell dysfunction and apoptosis, exacerbating insulin deficiency. Additionally, misfolded amylin, a protein co-secreted with insulin, can aggregate into toxic amyloid fibrils in the pancreas, further impairing beta-cell function.
These protein misfolding events create a vicious cycle of ER stress, beta-cell loss, and worsening hyperglycemia, driving the progression of T2D.