Proteinopathies
By Aarav Ghate | 1 October 2024
Neurodegenerative diseases (NDDs) are characterised by progressive deterioration of parts of the nervous system, such as the neurons, their synapses or glial cells. In some NDDs, this may be caused by deposition of proteins in the nervous system. In particular, when a protein misfolding leads to its deposition, it is called a proteinopathy.
Since proteins are long polymers, they form characteristic three dimensional structures in order to remain compact. This is known as protein folding. Generally, a protein will spontaneously fold into a structure that is the least energetic thermodynamically. This particular structure allows parts of the protein to interact with other molecules and receptors in the cell.
However, in certain cases, there may be two structures that are vastly different structurally, but have comparable energies. While one structure is the native one in the body and has a particular function, the other may be useless or even toxic. The body has developed molecules known as ‘chaperones’, which bind to the proteins and allow them to fold only in the correct structure by inhibiting the pathway that forms alternative, unwanted structure. However, given the large number of proteins present in the body, some still misfold due to random chance and form linear or fibrillar aggregates known as amyloid deposits.
A formation of amyloid deposits (due to misfolding of amyloid beta protein) in the nervous system leads to proteinopathies, such as Alzheimer’s Disease, Huntington’s Disease and Parkinson’s Disease. In some cases, the misfolding of one protein may catalyse misfolding of other proteins surrounding it, leading to a feedback loop. Prion diseases are proteinopathies that spread via ‘infectious’ proteins. These diseases are caused by toxic protein deposits which convert neighbouring proteins to toxic conformations. The risk of being affected by proteinopathies increases significantly with age, perhaps due to an increased frequency of misfolded protein aggregates.
Treatment strategies for proteinopathies involve preventing the formation of further aggregates by targeting proteins that are specific to a disease (for example, beta-amyloid protein in Alzheimer’s). Drugs that inhibit accumulation and promote chaperone expression could be potential treatments in the future. Vaccines which act against aggregation may also play a significant role.
References:
- Reynaud, E. Protein Misfolding and Degenerative Diseases. Nature Education, (2010).
- Kovacs GG, Molecular Pathology of Neurodegenerative Diseases: Principles and Practice, J Clinical Path, (2019)