Misfolded Proteins and Human Diseases

Abstract

Though protein folding is a regular phenomenon inside the cellular milieu, slight differences in the folding pattern of proteins may lead to disease-causing forms. Many diseases have been identified that are caused by these misfolded macromolecules and a considerable amount of focus is still directed towards better understanding of the processes that lead to these misfolded structures. Further progress in the field of how soluble proteins begin to misfold and how resultant oligomers begin dysfunction offers exciting prospects for specific molecular intervention.

Proteins Associated with Immunopurified Granules from a Model Pancreatic Islet β-Cell System: Proteomic Snapshot of an Endocrine Secretory Granule

“…Human amylin, which is cosecreted with insulin, can aggregate in vivo and form amyloid plaques that characteristically occur in the pancreatic islets in T2DM, which are similar to those in Alzheimer's disease and other amyloidassociated diseases such as Parkinson's and Huntington's diseases. 13,56 At high amylin concentrations, aberrant folding occurs independently of protein convertases (PC2, or PC1/3), to potentially seed amyloid fibrils that result in plaques. [57][58][59] During its transition from oligomers through proto-fibrils to insoluble fibrils, human amylin misfolding can elicit cytotoxic processes that cause or result in β-cell death.…”

“…The abundance of chaperones in β-cell granules highlights their likely significance for preserving intact and regulated protein secretion of the hormones, insulin and amylin, and for protecting the cell from the biological effects of protein misfolding. Human amylin, which is cosecreted with insulin, can aggregate in vivo and form amyloid plaques that characteristically occur in the pancreatic islets in T2DM, which are similar to those in Alzheimer’s disease and other amyloid-associated diseases such as Parkinson’s and Huntington’s diseases. , At high amylin concentrations, aberrant folding occurs independently of protein convertases (PC2, or PC1/3), to potentially seed amyloid fibrils that result in plaques. − During its transition from oligomers through proto-fibrils to insoluble fibrils, human amylin misfolding can elicit cytotoxic processes that cause or result in β-cell death . This process can result in decreased pancreatic β-cell mass and insulin secretion capacity, resulting in hyperglycaemia and ultimately T2DM .…”

Effect of an amyloidogenic sequence attached to yellow fluorescent protein

“…However, it is now clear that the proteins also tend to be associated into aggregates such as amyloid fibrils under various conditions. Depositions of amyloid fibrils formed by particular proteins are found in specific organs of patients suffering from amyloid diseases 1–3. However, some proteins that are apparently unconnected to any particular disease state also form fibrillar aggregates similar to amyloid fibrils under certain conditions 4–10.…”

Important Contributions of a New Quantitative Preparative Native Continuous Polyacrylamide Gel Electrophoresis (QPNC-PAGE) Procedure for Elucidating Metal Cofactor Metabolisms in Protein-Misfolding Diseases - A Theory

“…Furthermore, pathological disruption of metal trafficking inside a cell is probably a major reason for conformational changes in protein-misfolding diseases. Thereby, inactive metallochaperone proteins that protect and guide metal ions to targets could perhaps play a decisive role [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22].…”