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 Alzheimers disease, Parkinsons disease and Huntingtons 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.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. Weaponization
Prions could theoretically be employed as a weaponized agent. With potential fatality rates of 100%, prions could be an effective bio-weapon. An unfavorable aspect is prions very long incubation periods. Persistent heavy exposure of prions to the intestine might shorten the overall onset. Another aspect of using prions in warfare is the difficulty of detection and decontamination. History
In the 18th and 19th centuries, exportation of sheep from Spain was observed to coincide with a disease called scrapie.
Griffith proposed three ways in which a protein could be a pathogen.In the first hypothesis, he suggested that if the protein is the product of a normally suppressed gene, and introducing the protein could induce the genes expression, that is, wake the dormant gene up, then the result would be a process indistinguishable from replication, as the genes expression would produce the protein, which would then go wake the gene up in other cells. His second hypothesis forms the basis of the modern prion theory, and proposed that an abnormal form of a cellular protein can convert normal proteins of the same type into its abnormal form, thus leading to replication. His third hypothesis proposed that the agent could be an antibody if the antibody was its own target antigen, as such an antibody would result in more and more antibody being produced against itself. However, Griffith acknowledged that this third hypothesis was unlikely to be true due to the lack of a detectable immune response.Francis Crick recognized the potential significance of the Griffith protein-only hypothesis for scrapie propagation in the second edition of his "Central dogma of molecular biology" (1970): While asserting that the flow of sequence information from protein to protein, or from protein to RNA and DNA was "precluded", he noted that Griffiths hypothesis was a potential contradiction (although it was not so promoted by Griffith).