A large number of neurodegenerative diseases in humans result from protein misfolding and aggregation. Protein misfolding is believed to be the primary cause of Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Creutzfeldt-Jakob disease, cystic fibrosis, Gaucher’s disease and many other degenerative and neurodegenerative disorders.
What is Misfolding of Protein?
Misfolded proteins result when a protein follows the wrong folding pathway or energy-minimizing funnel, and misfolding can happen spontaneously.
For many proteins, the most prominent structural motif of the functional protein in its native conformation is known as the alpha helix, a right-handed spiral coil. When a protein becomes toxic, an extensive conformational change occurs and it acquires a motif known as the beta sheet.
The beta sheet conformation also exists in many functional native proteins, such as the immunoglobulins, but the transition from alpha helix to beta sheet is characteristic of amyloid deposits. The abnormal conformational transition from alpha helix to beta sheet exposes hydrophobic amino acid residues and promotes protein aggregation.
Why a protein becomes toxic and an extensive conformational change occurs?
Most of the time, only the native conformation is produced in the cell. But as millions and millions of copies of each protein are made during our lifetimes, sometimes a random event occurs and one of these molecules follows the wrong path, changing into a toxic configuration.
This kind of conformational change is most likely to occur in proteins that have repetitive amino acid motifs, such as polyglutamine; such is the case in Huntington’s disease.
What are infective conformations?
Remarkably, the toxic configuration is often able to interact with other native copies of the same protein and catalyze their transition into the toxic state. Because of this ability, they are known as infective conformations.
The newly made toxic proteins repeat the cycle in a self-sustaining loop, amplifying the toxicity and thus leading to a catastrophic effect that eventually kills the cell or impairs its function. A prime example of proteins that catalyze their own conformational change into the toxic form is the prion proteins.
What are Chaperones?
Under normal circumstances, the cell has mechanisms to prevent proteins from folding incorrectly, as well as to get rid of misfolded proteins. Proteins that have problems achieving their native configuration are helped by chaperones to fold properly, using energy from ATP. Chaperones can avoid the conformational change to beta sheet structure and the aggregation of these altered proteins; thus they seem fundamental to the prevention of protein misfolding.
What are amyloid diseases and their examples?
Accumulation of misfolded proteins can cause disease and these diseases are known as amyloid diseases. They are very common. The most prevalent one is Alzheimer’s disease, which affects about 10 percent of the adult population over sixty-five years old in North America. Parkinson’s disease and Huntington’s disease have similar amyloid origins. These diseases can be sporadic (occurring without any family history) or familial (inherited).
Why the risk of getting neurodegenerative diseases increases dramatically with age?
Regardless of the type, the risk of getting any of the neurodegenerative diseases increases dramatically with age. The mechanistic explanation for this correlation is that as we age (or as a result of mutations), the delicate balance of the synthesis, folding, and degradation of proteins is perturbed, resulting in the production and accumulation of misfolded proteins that form aggregates.
What are the environmental factors known to increase the risk of protein misfolding and resulting degenerative diseases?
Among the environmental factors known to increase the risk of suffering degenerative diseases is exposure to substances that affect the mitochondria, increasing the amount of oxidative damage to proteins. However, it is clear that no single environmental factor determines the onset of these disorders.
What are the genetic factors known to increase the risk of protein misfolding and resulting degenerative diseases?
There are genetic factors known to increase the risk of protein misfolding and resulting degenerative diseases . For example, in the simplest forms of familial Parkinson’s disease, mutations are associated with dominant forms of the disease. This means that an individual with a single copy of a defective gene will develop the disease, yet two copies of the defective gene are required for recessive forms of the disease to develop.
In the case of Alzheimer’s disease, and for other less common neurodegenerative diseases, the genetics can be even more complicated, since different mutations of the same gene and combinations of these mutations may differently affect disease risk .
