Editing Protein folding (section)

== Protein misfolding and neurodegenerative disease ==
{{Main|Proteopathy}}
A protein is considered to be [[protein misfolding|misfolded]] if it cannot achieve its normal native state. This can be due to mutations in the amino acid sequence or a disruption of the normal folding process by external factors.<ref name="Chaudhuri_2006"/> The misfolded protein typically contains [[Beta sheet|β-sheets]] that are organized in a supramolecular arrangement known as a cross-β structure. These β-sheet-rich assemblies are very stable, very insoluble, and generally resistant to proteolysis.<ref name="Soto_2006">{{cite journal | vauthors = Soto C, Estrada L, Castilla J | title = Amyloids, prions and the inherent infectious nature of misfolded protein aggregates | journal = Trends in Biochemical Sciences | volume = 31 | issue = 3 | pages = 150–5 | date = March 2006 | pmid = 16473510 | doi = 10.1016/j.tibs.2006.01.002 }}</ref> The structural stability of these fibrillar assemblies is caused by extensive interactions between the protein monomers, formed by backbone hydrogen bonds between their β-strands.<ref name="Soto_2006" /> The misfolding of proteins can trigger the further misfolding and accumulation of other proteins into aggregates or oligomers. The increased levels of aggregated proteins in the cell leads to formation of [[amyloid]]-like structures which can cause degenerative disorders and cell death.<ref name="Chaudhuri_2006">{{cite journal | vauthors = Chaudhuri TK, Paul S | title = Protein-misfolding diseases and chaperone-based therapeutic approaches | journal = The FEBS Journal | volume = 273 | issue = 7 | pages = 1331–49 | date = April 2006 | pmid = 16689923 | doi = 10.1111/j.1742-4658.2006.05181.x | s2cid = 23370420 | doi-access = free }}</ref> The amyloids are fibrillary structures that contain intermolecular hydrogen bonds which are highly insoluble and made from converted protein aggregates.<ref name="Chaudhuri_2006" /> Therefore, the proteasome pathway may not be efficient enough to degrade the misfolded proteins prior to aggregation. Misfolded proteins can interact with one another and form structured aggregates and gain toxicity through intermolecular interactions.<ref name="Chaudhuri_2006" />

Aggregated proteins are associated with [[prion]]-related illnesses such as [[Creutzfeldt–Jakob disease]], [[bovine spongiform encephalopathy]] (mad cow disease), amyloid-related illnesses such as [[Alzheimer's disease]] and [[familial amyloid cardiomyopathy]] or [[Familial amyloid polyneuropathy|polyneuropathy]],<ref name="pmid12560553">{{cite journal | vauthors = Hammarström P, Wiseman RL, Powers ET, Kelly JW | title = Prevention of transthyretin amyloid disease by changing protein misfolding energetics | journal = Science | volume = 299 | issue = 5607 | pages = 713–6 | date = January 2003 | pmid = 12560553 | doi = 10.1126/science.1079589 | bibcode = 2003Sci...299..713H | s2cid = 30829998 }}</ref> as well as intracellular aggregation diseases such as [[Huntington's]] and [[Parkinson's disease]].<ref name="Selkoe:03" /><ref name="ChitiDobson">{{cite journal | vauthors = Chiti F, Dobson CM | title = Protein misfolding, functional amyloid, and human disease | journal = Annual Review of Biochemistry | volume = 75 | pages = 333–66 | year = 2006 | pmid = 16756495 | doi = 10.1146/annurev.biochem.75.101304.123901 | s2cid = 23797549 }}</ref> These age onset degenerative diseases are associated with the aggregation of misfolded proteins into insoluble, extracellular aggregates and/or intracellular inclusions including cross-β [[amyloid]] [[fibril]]s. It is not completely clear whether the aggregates are the cause or merely a reflection of the loss of protein homeostasis, the balance between synthesis, folding, aggregation and protein turnover. Recently the [[European Medicines Agency]] approved the use of [[Tafamidis]] or Vyndaqel (a kinetic stabilizer of tetrameric transthyretin) for the treatment of transthyretin amyloid diseases. This suggests that the process of amyloid fibril formation (and not the fibrils themselves) causes the degeneration of post-mitotic tissue in human amyloid diseases.<ref name="pmid16359163">{{cite journal | vauthors = Johnson SM, Wiseman RL, Sekijima Y, Green NS, Adamski-Werner SL, Kelly JW | title = Native state kinetic stabilization as a strategy to ameliorate protein misfolding diseases: a focus on the transthyretin amyloidoses | journal = Accounts of Chemical Research | volume = 38 | issue = 12 | pages = 911–21 | date = December 2005 | pmid = 16359163 | doi = 10.1021/ar020073i }}</ref> Misfolding and excessive degradation instead of folding and function leads to a number of [[proteopathy]] diseases such as [[antitrypsin]]-associated [[emphysema]], [[cystic fibrosis]] and the [[lysosomal storage diseases]], where loss of function is the origin of the disorder. While protein replacement therapy has historically been used to correct the latter disorders, an emerging approach is to use [[pharmaceutical chaperones]] to fold mutated proteins to render them functional.