Protein Misfolding & Disease

Proteins generally fold in a specific region of the cell known as the endoplasmic reticulum, or ER. The cell has quality control mechanisms that ensure that proteins are folded into their correct three-dimensional shape before they can move from the ER to the appropriate destination in the cell, a process generally referred to as protein trafficking. Misfolded proteins are often eliminated by the quality control mechanisms after initially being retained in the ER. In certain instances, misfolded proteins can accumulate in the ER instead of being eliminated.

The retention of misfolded proteins in the ER interrupts their proper trafficking, and the resulting reduced biological activity can lead to impaired cellular function and ultimately to disease. In addition, the accumulation of misfolded proteins in the ER may lead to various types of stress on cells, which may also contribute to cellular dysfunction and disease.

Depending on the disease, several types of problems may result from protein misfolding, including:

Loss of Protein Function
Proteins are created for the purpose of performing a specific biological function. Misfolded proteins that are retained in the ER are unable to perform their function, disrupting the normal biological activity of the cell. For example, many of the mutations underlying Fabry disease result in a folding defect in an enzyme called alpha-galactosidase A (α-GAL), causing it to be retained in the ER and prematurely degraded. Consequently, the enzyme is unable to perform its normal function, which is to travel to the lysosome in the cell and metabolize a complex lipid called globotriaosylceramide (GL-3). As a result, GL-3 accumulates in the cells and leads to a variety of symptoms, including pain, clouded vision, kidney failure, and an increased risk of heart attack and stroke.

Aggregation or Accumulation of Misfolded Protein
The ER quality control mechanisms recognize misfolded proteins and retain them until they are properly folded. Eventually, misfolded proteins will be exported from the ER to be degraded by the proteasomes via the cell’s own internal degradation process. Accumulation and/or aggregation of misfolded proteins can disrupt and overload this degradation process, resulting in a broader disruption of cellular trafficking and other vital cellular functions. For example, α-1-antitrypsin deficiency is a disease characterized by a deficiency in functioning α-1-antitrypsin due to misfolding. This mutant protein is known to accumulate and aggregate in liver cells creating cellular stress that can lead to severe liver disease. Toxic protein accumulation/aggregation also contributes to the pathology of conditions such as Alzheimer’s and Parkinson’s diseases.