Editing Prion (section)

== In other diseases ==
Prion-like domains have been found in a variety of other mammalian proteins. Some of these proteins have been implicated in the ontogeny of age-related neurodegenerative disorders such as [[amyotrophic lateral sclerosis]] (ALS), [[Frontotemporal lobar degeneration|frontotemporal lobar degeneration with ubiquitin-positive inclusions]] (FTLD-U), [[Alzheimer's disease]], [[Parkinson's disease]], and [[Huntington's disease]].<ref name="King 2012">{{cite journal | vauthors = King OD, Gitler AD, Shorter J | title = The tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease | journal = Brain Research | volume = 1462 | pages = 61–80 | date = June 2012 | pmid = 22445064 | pmc = 3372647 | doi = 10.1016/j.brainres.2012.01.016 }}</ref><ref name="Goedert">{{cite journal | vauthors = Goedert M | title = NEURODEGENERATION. Alzheimer's and Parkinson's diseases: The prion concept in relation to assembled Aβ, tau, and α-synuclein | journal = Science | volume = 349 | issue = 6248 | pages = 1255555 | date = August 2015 | pmid = 26250687 | doi = 10.1126/science.1255555 | s2cid = 206558562 }}</ref><ref name="Olanow"/> They are also implicated in some forms of systemic [[amyloidosis]] including [[AA amyloidosis]] that develops in humans and animals with inflammatory and infectious diseases such as [[tuberculosis]], [[Crohn's disease]], [[rheumatoid arthritis]], and [[HIV/AIDS]]. AA amyloidosis, like prion disease, may be transmissible.<ref>{{cite journal | vauthors = Murakami T, Ishiguro N, Higuchi K | title = Transmission of systemic AA amyloidosis in animals | journal = Veterinary Pathology | volume = 51 | issue = 2 | pages = 363–371 | date = March 2014 | pmid = 24280941 | doi = 10.1177/0300985813511128 | doi-access = free }}</ref> This has given rise to the 'prion paradigm', where otherwise harmless proteins can be converted to a pathogenic form by a small number of misfolded, nucleating proteins.<ref name="Jucker 13">{{cite journal | vauthors = Jucker M, Walker LC | title = Self-propagation of pathogenic protein aggregates in neurodegenerative diseases | journal = Nature | volume = 501 | issue = 7465 | pages = 45–51 | date = September 2013 | pmid = 24005412 | pmc = 3963807 | doi = 10.1038/nature12481 | bibcode = 2013Natur.501...45J }}</ref>

The definition of a prion-like domain arises from the study of fungal prions. In yeast, prionogenic proteins have a portable prion domain that is both necessary and sufficient for self-templating and protein aggregation. This has been shown by attaching the prion domain to a reporter protein, which then aggregates like a known prion. Similarly, removing the prion domain from a fungal prion protein inhibits prionogenesis. This modular view of prion behaviour has led to the hypothesis that similar prion domains are present in animal proteins, in addition to PrP.<ref name="King 2012"/> These fungal prion domains have several characteristic sequence features. They are typically enriched in asparagine, glutamine, tyrosine and glycine residues, with an asparagine bias being particularly conducive to the aggregative property of prions. Historically, prionogenesis has been seen as independent of sequence and only dependent on relative residue content. However, this has been shown to be false, with the spacing of prolines and charged residues having been shown to be critical in amyloid formation.<ref name="Alberti, 2009">{{cite journal | vauthors = Alberti S, Halfmann R, King O, Kapila A, Lindquist S | title = A systematic survey identifies prions and illuminates sequence features of prionogenic proteins | journal = Cell | volume = 137 | issue = 1 | pages = 146–158 | date = April 2009 | pmid = 19345193 | pmc = 2683788 | doi = 10.1016/j.cell.2009.02.044 }}</ref>

Bioinformatic screens have predicted that over 250 human proteins contain prion-like domains (PrLD). These domains are hypothesized to have the same transmissible, amyloidogenic properties of PrP and known fungal proteins. As in yeast, proteins involved in gene expression and RNA binding seem to be particularly enriched in PrLD's, compared to other classes of protein. In particular, 29 of the known 210 proteins with an RNA recognition motif also have a putative prion domain. Meanwhile, several of these RNA-binding proteins have been independently identified as pathogenic in cases of ALS, FTLD-U, Alzheimer's disease, and Huntington's disease.<ref name="Eisenberg2012"/>

=== 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>