Editing Prion (section)

=== Role in neurodegenerative disease ===
The pathogenicity of prions and proteins with prion-like domains is hypothesized to arise from their self-templating ability and the resulting exponential growth of amyloid fibrils. The presence of [[amyloid]] fibrils in patients with degenerative diseases has been well documented. These amyloid fibrils are seen as the result of pathogenic proteins that self-propagate and form highly stable, non-functional aggregates.<ref name="Eisenberg2012">{{cite journal | vauthors = Eisenberg D, Jucker M | title = The amyloid state of proteins in human diseases | journal = Cell | volume = 148 | issue = 6 | pages = 1188–1203 | date = March 2012 | pmid = 22424229 | pmc = 3353745 | doi = 10.1016/j.cell.2012.02.022 }}</ref> While this does not necessarily imply a causal relationship between amyloid and degenerative diseases, the toxicity of certain amyloid forms and the overproduction of amyloid in familial cases of degenerative disorders supports the idea that amyloid formation is generally toxic.<ref>{{cite journal | vauthors = Ayers JI, Prusiner SB | title = Prion protein - mediator of toxicity in multiple proteinopathies | journal = Nature Reviews. Neurology | volume = 16 | issue = 4 | pages = 187–8 | date = April 2020 | pmid = 32123368 | doi = 10.1038/s41582-020-0332-8 | s2cid = 211728879 }}</ref>

Specifically, aggregation of [[TARDBP|TDP-43]], an RNA-binding protein, has been found in ALS/MND patients, and mutations in the genes coding for these proteins have been identified in familial cases of ALS/MND. These mutations promote the misfolding of the proteins into a prion-like conformation. The misfolded form of TDP-43 forms cytoplasmic inclusions in affected neurons, and is found depleted in the nucleus. In addition to ALS/MND and FTLD-U, TDP-43 pathology is a feature of many cases of Alzheimer's disease, Parkinson's disease and Huntington's disease. The misfolding of TDP-43 is largely directed by its prion-like domain. This domain is inherently prone to misfolding, while pathological mutations in TDP-43 have been found to increase this propensity to misfold, explaining the presence of these mutations in familial cases of ALS/MND. As in yeast, the prion-like domain of TDP-43 has been shown to be both necessary and sufficient for protein misfolding and aggregation.<ref name="King 2012"/>

Similarly, pathogenic mutations have been identified in the prion-like domains of heterogeneous nuclear riboproteins hnRNPA2B1 and hnRNPA1 in familial cases of muscle, brain, bone and motor neuron degeneration. The wild-type form of all of these proteins show a tendency to self-assemble into amyloid fibrils, while the pathogenic mutations exacerbate this behaviour and lead to excess accumulation.<ref name="Kim 2013">{{cite journal | vauthors = Kim HJ, Kim NC, Wang YD, Scarborough EA, Moore J, Diaz Z, MacLea KS, Freibaum B, Li S, Molliex A, Kanagaraj AP, Carter R, Boylan KB, Wojtas AM, Rademakers R, Pinkus JL, Greenberg SA, Trojanowski JQ, Traynor BJ, Smith BN, Topp S, Gkazi AS, Miller J, Shaw CE, Kottlors M, Kirschner J, Pestronk A, Li YR, Ford AF, Gitler AD, Benatar M, King OD, Kimonis VE, Ross ED, Weihl CC, Shorter J, Taylor JP | title = Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS | journal = Nature | volume = 495 | issue = 7442 | pages = 467–473 | date = March 2013 | pmid = 23455423 | pmc = 3756911 | doi = 10.1038/nature11922 | bibcode = 2013Natur.495..467K }}</ref>