Prion

[[File:Prion trafficking- scrapie mouse (5661846150).jpg|thumb|right|165px|Four nerve cells in a mouse; the red parts show prion proteins, which are transmitted along neurites (projections between cells).]]
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'''Prions''' are misfolded [[protein]]s with the ability to transmit their misfolded shape onto normal variants of the same protein.<ref name=niaid1>[https://www.niaid.nih.gov/diseases-conditions/prion-diseases Prion Diseases] ''National Institute of Allergy and Infectious Diseases'.</ref> Prions are the cause of many fatal diseases. While most prion diseases are neurological, some can affect other parts of the body.<ref name=niaid1/><ref>[https://www.nejm.org/doi/full/10.1056/nejmoa1214747 A Novel Prion Disease Associated with Diarrhea and Autonomic Neuropathy] ''New England Journal of Medicine''</ref><ref>[https://n.neurology.org/content/90/15_Supplement/P1.175 Peripheral Neuropathy in Patients with Prion Disease] ''Neurology''</ref> Prions are most known for their role in transmissible spongiform encephalopathies (TSEs), but they are the cause of other diseases including multiple system atrophy, Alzheimer's disease, Huntington's disease, and some forms of amyloidosis.<ref name="Alzheimer's disease is a 'double prion' disorder">[https://www.ucsf.edu/news/2019/05/414326/alzheimers-disease-double-prion-disorder-study-shows Alzheimer’s Disease is a ‘Double-Prion Disorder,’ Study Shows]. ''University of California San Francisco Research.'' Nicholas W, 1 May 2019.</ref>

==Pathology of prions==
Proteins, when exposed to [[enzyme]]s that break them down (proteases), are chopped up into small bits (technically, the protein is protease-sensitive). However, when the normal prion protein (PrP<sup>C</sup>) folding occurs, the proteins may misfold into the pathogenic/infectious form (PrP<sup>Sc</sup>), after which it then causes disease.<ref>[https://science.sciencemag.org/content/300/5621/917.abstract A View from the Top--Prion Diseases from 10,000 Feet] by Suzette A. Priola (2003) ''Science'' doi:10.1126/science.1085920.</ref> This has three effects:<ref>[https://www.researchgate.net/publication/7001642_Doppel_More_rival_than_double_to_prion Doppel: More rival than double to prion] by Kefeng Qin et al. (2006) ''Neuroscience'' 141(1):1-8. doi:10.1016/j.neuroscience.2006.04.057.</ref>
#The protein is highly protease-resistant
#The protein has the ability to cause other variants of the same protein to adopt their form
#The prions become the most potent known neurotoxin
Once a misfolded prion protein (PrP<sup>Sc</sup>) comes into contact with normal protein prion protein (PrP<sup>C</sup>) it converts the PrP<sup>C</sup> into PrP<sup>Sc</sup> (a domino effect). Prion infections are currently untreatable, although some people seem to have [[evolution|evolved]] a degree of resistance (most notably the {{wpl|Fore people}} due to consistent encounters with kuru over several generations, some of whom went 45 years after initial contact before becoming symptomatic).<ref>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4043168/pdf/rsif20130331.pdf Epidemiological mechanisms of [[genetic]] resistance to kuru] by Katherine E. Atkins et al. (2013) ''Journal of the Royal Society Interface'' 10(85): 20130331. doi:10: 20130331.</ref> While prions do not appear to be capable of airborne transmission naturally, a study showed that an artificial prion aerosol can cause certain death to mice within a minute of exposure.<ref>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3554158/ Aerosol Transmission of Chronic Wasting Disease in White-Tailed Deer] by Nathaniel D. Denkers, Jeanette Hayes-Klug, Kelly R. Anderson, Davis M. Seelig, Nicholas J. Haley, Sallie J. Dahmes, David A. Osborn, Karl V. Miller, Robert J. Warren, Candace K. Mathiason, and Edward A. Hoover, February 2013, ''PubMed''</ref> <ref>[https://www.wired.com/2011/01/airborne-prions-disease/ Airborne Prions Make for 100 Percent Lethal Whiff] by Dave Mosher, January 13, 2011, ''Wired''</ref> This opens the doors to a potential prion [[terrorist]] attack; however, there is very little to fear, as the 30-year incubation time would make the spike in cases hard to link to the attack as well as an unappealing method for a terrorist.

Prions are extremely resistant to all forms of destruction. They can survive incineration, [[ionizing radiation]], autoclaving, and they can persist in soil for hundreds of years, remaining infectious.<ref>[https://blogs.scientificamerican.com/artful-amoeba/prions-are-forever/ Prions Are Forever] by Jennifer Frazer, April 9, 2018, ''Scientific American''</ref> Prions are similar to radioactive fallout, if fallout was ''infectious and near-undetectable''. They also stick to stainless steel within seconds.

While PrP is the most famous prion, (literally: prion protein), other proteins can become prions in a similar way. Multiple system atrophy is caused by prion isoforms of α-synuclein.<ref>[https://pubmed.ncbi.nlm.nih.gov/28213437/ α-Synuclein: Multiple System Atrophy Prions] by Amanda L Woerman, Joel C Watts, Atsushi Aoyagi, Kurt Giles, Lefkos T Middleton, and Stanley B Prusiner, July 2018, ''PubMed''</ref> Alzheimer's disease is also a prion disease, but it's especially notable not just because 450,000-700,000 fall victim to this disease every year, but because evidence shows that the prions involved can misfold ''other types of proteins.'' The prions that cause Alzheimer's are beta-amyloid and tau.<ref name="Alzheimer's disease is a 'double prion' disorder"></ref>

==Transmission==
There are three types of prion disease — infectious, sporadic, and genetic. 
#In the infectious form, one gets the disease by contact with infected materials or tissues. The nervous system tissue is the most infectious material. Prion disease can spread by blood, and prion-laced blood transfusions have been linked to at least 4 deaths.<ref>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2725807/</ref> Infectious also covers iatrogenic transmission (getting the disease from infected [[medical]] instruments — don't think too hard about where that endoscope went last!).  
#The sporadic form occurs when proteins misfold for a reason not yet known to medical science. The most common theory is that proteins misfold all the time, but the faulty proteins are broken down by proteases. However, prions are resistant to proteases, so they fail to be broken down, and spread their corrupted form. Some scientists believe a toxin could amplify this process.
#For the genetic prion diseases, prions are caused by a [[mutation]] of the PRNP [[human]] protein [[gene]]. Genetic prion diseases are the rarest out of the three of them. The most notable genetic prion disease is fatal familial insomnia, a genetic disorder present in only 30 families worldwide.

==Transmissible spongiform encephalopathies==
'''
Contagious sponge-brain disease
''' '''Transmissible spongiform encephalopathies''' are neurodegenerative [[brain]] diseases exclusively caused by prion isoforms of the prion protein (confusing, right?) called PrP<sup>Sc</sup> or PrP<sup>res</sup>.<ref>[https://www.cdc.gov/prions/index.html Prion Diseases]. ''Centers for Disease Control and Prevention.'' 9 October 2018.</ref>  They are also protease resistant, and extremely neurotoxic. They affect humans and [[animals]] alike, and have been shown to cross the [[species]] barrier easily.<ref>[https://www.bbc.com/news/uk-45906585 'Mad Cow Disease': What is BSE?] ''BBC News.'' 18 October 2018.</ref> They have extremely long incubation periods; in humans they can be up to 50 years. The name 'spongiform encephalopathy' comes from the fact that they ''literally rip holes in your brain.'' Symptoms in humans include dementia, ataxia, depression, paralysis, and always lead to [[death]]. In the [[US]], there are about 350 cases per year.<ref>[https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-sheets/Creutzfeldt-Jakob-Disease-Fact-Sheet Creutzfeldt-Jakob Disease Fact Sheet]. ''National Institute of Neurological Disorders and Stroke.'' 13 March 2020.</ref>

===In humans===
====Creutzfeldt-Jakob disease====
<!-- Please do not add variant CJD into this section. It is a different disease caused by different forms of PrP, specifically PrPBSE. -->
Creutzfeldt-Jakob disease, also known as subacute spongiform encephalopathy, is a neurodegenerative brain disease that usually occurs in people between the ages of 50 and 65. Its symptoms include ataxia, dementia, speech issues, quadriplegia, and death is certain after 18 months, while most only survive 6. The incubation period is estimated at about 30 years.<ref>[https://www.cdc.gov/prions/cjd/index.html Creutzfeldt-Jakob Disease, Classic (CJD)]. ''Centers for Disease Control and Prevention.'' 9 October 2018.</ref> It has three forms, based on the way that the person was infected.

=====Sporadic=====
Sporadic CJD is just that — CJD without a known cause. This form makes up the majority of cases. Some [[scientists]] speculate that sporadic misfoldings are natural, but the faulty proteins are usually broken down. <ref>[https://www.nhs.uk/conditions/creutzfeldt-jakob-disease-cjd/causes/ Causes: Creutzfeldt-Jakob disease]. ''NHS UK.'' 14 June 2018.</ref> Others think it could be a [[toxin]], and there appears to be significant evidence to show that they can affect protein folding, but none conclusively tying it to TSEs or other prionopathies.<ref>[https://pubmed.ncbi.nlm.nih.gov/24970215/ Heavy metals and metalloids as a cause for protein misfolding and aggregation]. ''National Library of Medicine.'' Markus J. T., et al., 25 February 2014, doi:[https://doi.org/10.3390/biom4010252 10.3390/biom4010252].</ref><ref>[https://onlinelibrary.wiley.com/doi/10.1002/qua.26372 Evidence for protein misfolding in the presence of nanoplastics]. ''Wiley Online Library.'' Oldamur H., 24 June 2020, doi:[https://doi.org/10.1002/qua.26372 10.1002/qua.26372].</ref><ref>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2999683/ Gene expression in primary cultured astrocytes affected by aluminum: alteration of chaperons involved in protein folding]. ''Environ Health Prev Med.'' David A. A., et al., 22 June 2010, doi:[https://dx.doi.org/10.1007%2Fs12199-010-0161-2 10.1007/s12199-010-0161-2].</ref>

=====Iatrogenic=====
Iatrogenic CJD is when the exposure to prions is linked to a medical procedure. This can include tainted blood transfusions,<ref>[https://pubmed.ncbi.nlm.nih.gov/12388826/ Transmission of prion diseases by blood transfusion]. ''National Library of Medicine.'' Nora H. et al., November 2002, doi:[https://doi.org/10.1099/0022-1317-83-11-2897 10.1099/0022-1317-83-11-2897].</ref> contaminated neurosurgical tools,<ref>[https://pubmed.ncbi.nlm.nih.gov/23896549/ Iatrogenic Creutzfeldt-Jakob disease via surgical instruments]. ''National Library of Medicine.'' Jonathan G. T., et al., 27 July 2013, doi:[https://doi.org/10.1016/j.jocn.2013.01.007 10.1016/j.jocn.2013.01.007].</ref> infected organ transplants,<ref>https://pubmed.ncbi.nlm.nih.gov/24770619/</ref> and other medical procedures involving blood or brain matter transmission.

An epidemic of iCJD occurred after [[human growth hormone]] taken from cadavers became contaminated with prions. 226 cases of iCJD were linked to the faulty treatment, and the exposed patients also have a higher chance of contracting Alzheimer's disease.<ref>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3647424/ Iatrogenic Creutzfeldt-Jakob Disease from Commercial Cadaveric Human Growth Hormone]. ''US National Library of Medicine.'' Brian S. A., et al., April 2013, doi:[https://dx.doi.org/10.3201%2Feid1904.121504 10.3201/eid1904.121504].</ref>

=====Familial=====
Familial CJD is when a gene inherited from a parent is faulty, and produces abnormal prions. All familial TSEs are autosomal dominant mutations, meaning that only one copy of the mutated {{wpl|PRNP}} gene will cause the disease, and any [[children]] that the person has will have a 50% chance of carrying the gene. It is estimated that 5-15% of all cases of CJD are familial.<ref>[https://www.alzheimer-europe.org/Dementia/Other-forms-of-dementia/Infectious-diseases/Human-Prion-Diseases/Familial-CJD Familial CJD]. ''Alzheimer Europe.'' André D., Clive E., 9 October 2009.</ref>

====Variant Creutzfeldt-Jakob disease====
Variant CJD is a disease directly linked to the consumption of beef contaminated with [[bovine spongiform encephalopathy]].<ref>[https://www.cdc.gov/prions/vcjd/about.html About vCJD]. ''Centers for Disease Control and Prevention.'' 24 October 2019.</ref> Unlike CJD, it affects younger people, with the median age of onset being 28.<ref>[https://www.ecdc.europa.eu/en/vcjd/facts Facts about variant Creutzfeldt-Jakob disease]. ''European Center for Disease Prevention and Control.'' 26 June 2017.</ref> The symptoms are almost identical to CJD, but the prion involved is thought to be exactly the same isoform as the BSE-causing prion. Affected patients survive on average for 18 months, but the disease is still always fatal. However, one infected person survived for over ten years.<ref>[https://blogs.scientificamerican.com/unofficial-prognosis/three-bizarre-tales-of-medical-survivors-and-what-they-can-and-cannot-teach-us-about-medicine/ Three bizarre tales of medical survivors, and what they can (and cannot) teach us about medicine]. ''Scientific American.'' Ilana Y., 12 June 2012.</ref>

{{wpl|United Kingdom BSE outbreak|An epidemic of this variant in the UK}} killed 177 people, several [[cats]], and almost a million cows. The cause was infected meat and bone meal (MBM). The incineration process failed to destroy the resistant prion protein, and when cows ate the tainted food, they would become infected. Their remains were turned into MBM, causing the disease to spread rapidly.

====Fatal familial insomnia====
Fatal familial insomnia is a disease that is characterized by the ''complete inability to sleep'' i.e. living Hell. The first signs of the disease are progressive insomnia, which leads to the classic signs of a TSE. Eventually, the victim will not be able to [[sleep]]. Sleeping pills will just accelerate the progression of the symptoms, and as the name suggests, the disease is terminal.<ref>[https://rarediseases.org/rare-diseases/fatal-familial-insomnia Fatal Familial Insomnia]. ''National Organization for Rare Disorders.'' 2018.</ref> FFI is usually caused by a malformed gene, but very rarely, it can happen sporadically.<ref>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3934327/ Sporadic Fatal Insomnia in an Adolescent] by Jennifer L. Blase, MPH, Laura Cracco, PhD, Lawrence B. Schonberger, MD, Ryan A. Maddox, PhD, Yvonne Cohen, BS, Ignazio Cali, MS, and Ermias D. Belay, MD, March 2014, ''PubMed''</ref>

====Gerstmann-Sträussler-Scheinker syndrome====
Gerstmann-Sträussler-Scheinker syndrome is a familial TSE that occurs in people from the age of 35-50. The symptoms include progressive ataxia, dementia, slurred speech, abnormal [[eye]] movements, rigid muscles, deafness, and Parkinsonism (in some cases).<ref>[https://rarediseases.info.nih.gov/diseases/7690/gerstmann-straussler-scheinker-disease Gerstmann-Straussler-Scheinker syndrome] ''Genetic and Rare Diseases Information Center''</ref>

====Kuru====
Kuru, literally 'shaking disease' (from the Fore language), is a TSE associated with ritual mortuary [[cannibalism]]. Symptoms include the classic TSE symptoms, as well as shaking uncontrollably, and bouts of laughing (which is always quite mirthless), causing some to call it the 'laughing disease'. The {{wpl|Fore people}} had an epidemic of this disease due to them consuming the bodies of people who died.<ref>[https://www.ninds.nih.gov/Disorders/All-Disorders/Kuru-Information-Page Kuru] ''NIH''</ref>

====Variably-protease sensitive prionopathy====
Variably-protease sensitive prionopathy is a disease very similar to sCJD, but stands out due to all tests for CJD showing nothing in VPsPr patients. It is very hard to diagnose and commonly mistaken for CJD or Alzheimer's disease.<ref>[https://www.merckmanuals.com/professional/neurologic-disorders/prion-diseases/variably-protease-sensitive-prionopathy-vpspr Variably Protease-Sensitive Prionopathy (VPSPr)] by Brian Appleby, November 2022, ''Merck Manual''</ref>

===In animals===
====Bovine spongiform encephalopathy====
{{main|Bovine spongiform encephalopathy}}
Commonly known as mad cow disease, BSE is a prion disease affecting cows. It is extremely rare, however if infected meat and bone meal is fed to cows, it can spread very rapidly. BSE can spread to humans, and is called variant Creutzfeldt-Jakob disease. The UK had an epidemic caused by poor farming practices; meat and bone meal was fed to cows, and when the cows died from the disease, their remains were ground up into more MBM, causing the disease to spread exponentially. Almost a million cows, several cats, and 177 humans died in the epidemic.<ref>[https://www.cdc.gov/prions/bse/index.html Bovine Spongiform Encephalopathy (BSE), or Mad Cow Disease] ''CDC''</ref> Worryingly, a new variant of BSE, called atypical BSE, has been shown to be similar to sporadic CJD, however no link has been established between the two.<ref>[https://www.cidrap.umn.edu/news-perspective/2004/02/new-form-bse-resembles-sporadic-cjd New form of BSE resembles sporadic CJD] by Robert Roos, February 19, 2004, ''University of Minnesota''</ref>

====Scrapie====
Scrapie is a TSE affecting [[sheep]] and [[goats]]. It was the first prion disease ever, discovered in 1755 (though its relation to prions was not discovered until the 20<sup>th</sup> century).<ref>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1114482/ 1755 and all that: a historical primer of transmissible spongiform encephalopathy] by Paul Brown, and Raymond Bradley, December 19, 1998, ''PubMed''</ref> The signs of scrapie are abnormal gait, ataxia, and compulsive scraping.<ref>[https://scrapiecanada.ca/about-scrapie/ What is Scrapie?] ''Scrapie Canada''</ref> Scrapie does not appear to be able to infect humans, and the disease has been eradicated in most countries. It is extremely infectious, and a pen that housed infected sheep was disinfected with strong acids, repainted, and the metal was replaced. Sheep placed in it were infected within a year.<ref>[https://www.cfsph.iastate.edu/Factsheets/pdfs/transmissible_spongiform_encephalopathy.pdf Transmissible Spongiform Encephalopathies of Animals] October 2016, ''Institute for International Cooperation in Animal Biologics''</ref>

====Chronic wasting disease====
Chronic wasting disease is a TSE affecting deer. The symptoms include severe weight loss, loss of fear of humans, and fur loss. It is the most infectious of all TSEs, and has an {{wpl|Net reproduction rate|R0}} of '''''3.2'''''!<ref>[https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0140024 Empirical Estimation of R0 for Unknown Transmission Functions: The Case of Chronic Wasting Disease in Alberta] by Alex Potapov, Evelyn Merrill, Margo Pybus, and Mark A. Lewis, October 9, 2015, ''Plos One''</ref> Since the disease is 100% fatal, that means for every deer infected, approximately 3-4 deer will die. While this disease doesn't appear to affect humans, there is weak evidence linking it to clusters of CJD cases.<ref>[https://www.cdc.gov/prions/cwd/transmission.html Transmission|Wasting Disease] ''CDC''</ref><ref>[https://jamanetwork.com/journals/jamaneurology/fullarticle/780509 Creutzfeldt-Jakob Disease in Unusually Young Patients Who Consumed Venison] by Ermias D. Belay MD, Pierluigi Gambetti MD, and Lawrence B. Schonberger MD, October 2001, ''Journal of American Medicine''</ref> While the [[CDC]] says that the [[risk]] is minimal, it still recommends to take safety precautions, and not to eat infected meat.<ref>[https://www.cdc.gov/prions/cwd/prevention.html Prevention|Chronic Wasting Disease] ''CDC''</ref> Infected deer are still a danger to humans, as they have a tendency to stand in roads, which can pose a hazard for drivers.

====Other spongiform encephalopathies====
*Feline spongiform encephalopathy<ref>[https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/feline-spongiform-encephalopathy Feline Spongiform Encephalopathy] ''New England Journal of Medicine''</ref>
*Ungulate spongiform encephalopathy<ref>[https://pubmed.ncbi.nlm.nih.gov/22044871/ An overview of animal prion diseases] by Muhammad Imran, and Saqib Mahmood, November, 2011, ''PubMed''</ref>
*Primate spongiform encephalopathy<ref>[https://pubmed.ncbi.nlm.nih.gov/21266755/ Experimental transmission of bovine spongiform encephalopathy (BSE) to cynomolgus macaques, a non-human primate] by Fumiko Ono, Keiji Terao, Naomi Tase, Akio Hiyaoka, Atsushi Ohyama, Yukio Tezuka, Naomi Wada, Asuka Kurosawa, Yuko Sato, Minoru Tobiume, Ken'ichi Hagiwara, Yoshio Yamakawa, and Tetsutaro Sata, 2011, ''PubMed''</ref><ref group=note>Excluding humans, of course.</ref>
*Ostrich spongiform encephalopathy<ref>[https://pubmed.ncbi.nlm.nih.gov/1887441/ [Spongiform encephalopathy in a red-necked ostrich (Struthio camelus)]] by H A Schoon, D Brunckhorst, and J Pohlenz, June, 1991, ''PubMed''</ref><ref group=note>However, there is evidence showing this could be a virus instead of a prion.</ref>
*Camel spongiform encephalopathy<ref>[https://www.cidrap.umn.edu/news-perspective/2018/04/mad-camel-disease-new-prion-infection-causes-alarm 'Mad camel' disease? New prion infection causes alarm] by Stephanie Soucheray April 18, 2018, ''University of Minnesota''</ref>
*Transmissible mink encephalopathy<ref>[https://www.cfsph.iastate.edu/Factsheets/pdfs/transmissible_mink_encephalopathy.pdf Transmissable Mink Encephalopathy] by Anna Rovid Spickler, DVM, PhD, August 2016, ''Institute for International Cooperation in Animal Biologics''</ref>

==Non-TSE prion diseases==

===Alzheimer's disease===
Alzheimer's disease is a prion disease notable for 2 reasons: It is caused by 2 different prions, amyloid-beta and tau<ref>[https://pubmed.ncbi.nlm.nih.gov/24493463/ Amyloid-β and tau: the trigger and bullet in Alzheimer disease pathogenesis] by George S. Bloom, April 2014, ''PubMed''</ref>, and there are almost '''600,000 cases per year.''' Alzheimer's disease is the 6th leading cause of death in the US, and is the only disease in the top 10 causes of death that cannot be prevented or cured. One third of people over 85 are suffering from the disease, and every 66 seconds someone develops Alzheimer's.<ref>[https://www.alzheimers.net/resources/alzheimers-statistics 2019 Alzheimer’s Statistics] ''alzheimers.net''</ref>

The disease is universally fatal. While it's believed to be sporadic, there are many genetic factors that increase the chance you will be infected. Most people living with the disease are above the age of 60. The disease is neurodegenerative, and tends to set in much more rapidly if it begins prior to the age of 65. The flagship symptom of Alzheimer's disease is dementia. On an MRI, amyloid plaques can be seen to confirm the diagnosis. <ref>[https://www.cdc.gov/aging/aginginfo/alzheimers.htm Alzheimer’s Disease and Related Dementias] ''CDC''</ref>

===Multiple system atrophy===
Formerly known as Shy-Drager Syndrome, multiple system atrophy is a prion disease that affects the nervous system. The prion responsible is alpha-Synuclein<ref>[https://pubmed.ncbi.nlm.nih.gov/28213437/ α-Synuclein: Multiple System Atrophy Prions] by Amanda L Woerman, Joel C Watts, Atsushi Aoyagi, Kurt Giles, Lefkos T Middleton, and Stanley B Prusiner, July 2018, ''PubMed''</ref>. It is transmissible, and sporadic, meaning there is no known cause. The disease is very similar to {{wpl|Parkinson's disease}}, making diagnosis hard. The median age of onset is 55 years.<ref>[https://www.multiplesystematrophy.org/about-msa/ Multiple System Atrophy (MSA)] ''The MSA Coalition''</ref> There are 2 forms of MSA. Symptoms that are present in both forms include dizziness, loss of balance, a low pitched voice, fainting, urinary incontinence, and rigid muscles. The disease is universally fatal, with a survival time of 7 years.

The parkinsonian type of MSA is the most difficult to diagnose. All of the unique symptoms in MSA-P are the same as Parkinson's disease. The second type is the cerebellar form, known as MSA-C. MSA-C is similar to Creutzfeldt-Jakob disease in that its main symptom is ataxia. Difficulty swallowing, severe speech abnormalities, and abnormal eye movements are the distinguishing symptoms of MSA-C.<ref>[https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Multiple-System-Atrophy Multiple System Atrophy] ''NIH''</ref>

===Huntington’s disease===
Huntington's disease is a hereditary neurodegenerative prion disease of the brain. Unlike many genetic disorders it is a dominant allele, so one affected parent has at least a 50% chance of passing it on. It is characterized by a slow neurological decline, with the end result being the complete inability to move or function. Like other prion diseases, it is always fatal and incurable. The age of onset of the disease varies wildly, with onsets as early as 2 years of age, up to 85 years. Usually the disease manifests between age 30-60, though rarely it can set in during teenage years. Once symptoms appear, life expectancy is between 10 and 20 years. <ref>[https://medlineplus.gov/genetics/condition/huntington-disease Huntington's disease] ''MedlinePlus''</ref>

The disease has 5 distinct stages, with the first stage being very mild, and the fifth being end-of-life.<ref>[https://www.medicinenet.com/what_are_the_5_stages_of_huntingtons_disease/article.htm What Are the 5 Stages of Huntington’s Disease?] by Dr. Jasmine Shaikh, MD, July 22, 2022, ''MedicineNet''</ref>

====Stage 1: Before diagnosis====
The first stage is almost unnoticeable. Doctors are unable to diagnose the condition at this stage. Minor mood problems and thinking issues are the first symptoms.

====Stage 2: Early====
Affected people are usually formally diagnosed at this stage. Twitches and slight tremors are present, but they can be mistaken for stress. Simple tasks become difficult. Depression, anxiety, and anger issues become much worse. Eating becomes slightly more difficult, and insomnia and waking up during sleep occur. While the affected can usually drive to work and are able to complete tasks at work, they will need help doing some of their daily activities. 

====Stage 3: Moderate====
Walking becomes more difficult. Most people will need a wheelchair at this stage. Thinking is severely impaired. Depression becomes crippling, and sufferers will no longer be able to drive or work. Severe difficulty in swallowing is observed. People affected will need a full time caretaker as they are no longer able to carry out daily tasks. Insomnia becomes severe.

====Stage 4: Severe====
By this stage, walking is impossible and the affected become bedridden. Using the bathroom is impossible. They cannot talk, and it's extremely hard to sleep. A feeding tube becomes required. They are unable to do anything for themselves, and require 24/7 care. [[Euthanasia]] is a choice, as the person is completely unable to move and is in a lot of pain.

====Stage 5: End of life====
In Stage 5, the person is usually in a {{wpl|vegetative state}}. Like other prion diseases, Huntington's disease does not kill directly, and it's possible for the person to live several more years in a vegetative state. The usual cause of [[death]] is pneumonia due to aspiration of food, or the family deciding to take the person off of life support.

==Misinformation==
Unfortunately, there is a lot of [[Pseudoscience|misinformation and discredited science]] surrounding TSEs. 

===Spiroplasma===
While the [[scientific consensus]] is that all TSEs are caused by prions, one scientist has disputed this. Frank O. Bastian has published several papers claiming that the bacterium Spiroplasma is the true cause of TSEs, specifically CWD.<ref>[https://www.microbiologyresearch.org/content/journal/jmm/10.1099/jmm.0.47159-0 Spiroplasma spp. from transmissible spongiform encephalopathy brains or ticks induce spongiform encephalopathy in ruminants] Frank O. Bastian, Dearl E. Sanders, Will A. Forbes, Sue D. Hagius, Joel V. Walker, William G. Henk, Fred M. Enright and Philip H. Elzer, 1 September, 2007, ''Journal of Medical Microbiology'', ''Microbiology Society''</ref><ref>[https://www.biorxiv.org/content/10.1101/232074v1.full.pdf Data Analyses and new Findings Indicate a Primordial Neurotropic Pathogen 
Evolved into Infectious Causes of Several CNS Neurodegenerative Diseases] by William J. Todd, Lidiya Dubytska, Peter J. Mottram, Xiaochu Wu and 
Yuliya Y. Sokolova, December 11, 2017, ''bioRxiv''</ref> The evidence seems convincing - but there are many issues with his research.

No other scientists were able to replicate his findings. In addition, a study done in 2006 directly refutes the theory.<ref>[https://jcm.asm.org/content/44/1/91 Absence of Spiroplasma or Other Bacterial 16S rRNA Genes in Brain Tissue of Hamsters with Scrapie] by Irina Alexeeva, Ellen J. Elliott, Sandra Rollins, Gail E. Gasparich, Jozef Lazar, and Robert G. Rohwer, 1 January, 2016, ''Journal of Clinical Microbiology'', ''American Society for Microbiology''</ref> While he was able to cause CWD in deer by injecting them with Spiroplasma, he took the bacteria from the brain of deer already infected. This would almost certainly contaminate the sample with PrP<sup>Sc</sup>. Any disinfection procedure that would destroy the prions would also kill the bacteria. The bacteria infects plants, and any deer that ate the infected plants would become a carrier. However, they are likely asymptomatic.<ref>[https://pubmed.ncbi.nlm.nih.gov/9286068/ Spiroplasmas: infectious agents of plants, arthropods and vertebrates] by J M Bové August 8, 1997, ''PubMed''</ref> This explains the presence of the bacteria in CWD-infected deer. Since no uninfected deer were tested, there is no way to prove that the bacteria is only present in cases of CWD.

===60,000 cases===
A study by Laura Manuelidis showed that 13% of Alzheimer's disease cases were actually CJD.<ref>[https://www.upi.com/Science_News/2003/12/30/Mad-Cow-Linked-to-thousands-of-CJD-cases/47861072816318/ Mad Cow: Linked to thousands of CJD cases?] by Steve Mitchell, December 30, 2003, ''UPI''</ref> With over 500,000 cases of Alzheimer's per year,<ref>[https://www.brightfocus.org/alzheimers/article/alzheimers-disease-facts-figures Alzheimer’s Disease: Facts & Figures] ''BrightFocus Foundation''</ref> that could be up to 60,000 missed cases of CJD, per year. While the study is real, it suffers from a low sample size. They only tested 60 patients. A later study shows that while it is true that there are misdiagnosed CJD cases, the number is far lower. Out of 6,000 cases, 19 cases were shown to be a misdiagnosed TSE.<ref>[https://journals.sagepub.com/doi/pdf/10.1177/1533317515602218 Clinically Unsuspected Prion Disease Among Patients With Dementia Diagnoses in an Alzheimer’s Disease Database] by Ryan A. Maddox, PhD, J. L. Blase, MPH, N. D. Mercaldo, MS, A. R. Harvey, MSPH, L. B. Schonberger, MD, W. A. Kukull, PhD, and E. D. Belay, MD, 2015, ''SAGE''</ref> This would put the number at 1,584 more cases, if all 500,000 have the same error rate.

===COVID vaccine prion "study"===
{{main|COVID-19 pandemic}}
In May of 2022, a "study" was released linking CJD, a prion disease, to mRNA COVID-19 vaccines.<ref>[https://ijvtpr.com/index.php/IJVTPR/article/view/66 Towards the emergence of a new form of the neurodegenerative Creutzfeldt-Jakob disease: Twenty six cases of CJD declared a few days after a COVID-19 “vaccine” Jab] by Jean Claud Perez, Claire Moret-Chalmin and Luc Montagnier, January 12, 2023, ''International Journal of Vaccine Theory, Practice and Research''</ref> This study has not been [[peer-review]]ed, is full of informal language, unsourced content, grammatical errors, and broken formatting. It relies on a case of CJD detected after a man was infected with COVID-19. This case is real, but it was after the COVID virus, not the vaccine.{{citation needed}} It falsely links mRNA to prion diseases. One of the three co-authors, [[Luc Montagnier]] who had been suffering from [[Nobel disease]], died shortly before the study was released to the public.<ref>[https://www.theguardian.com/science/2022/feb/18/luc-montagnier-obituary Luc Montagnier obituary: French virologist who shared the Nobel prize as co-discoverer of HIV but championed the anti-vax movement in later life] by Georgina Ferry (Fri 18 Feb 2022 11.42 EST) ''The Guardian''.</ref> Montagnier died at age 89 of unknown causes, but that did not stop a [[conspiracy theorist]] claiming that he was murdered for exposing  the 'truth' about vaccines.<ref>[https://www.politifact.com/factchecks/2022/feb/23/facebook-posts/fact-checking-more-misinformation-about-luc-montag/ Luc Montagnier's death is linked to his "exposing" that there's HIV in the COVID-19 vaccine.] by Ciara O'Rourke (February 23, 2022) ''Politifact''.</ref>

==COVID-19 and TSEs==
COVID-19 has been linked to TSEs, by both scientists, and cranks.

===Acceleration of prion disease pathogenesis===
A paper released in July 2020 showed a case of sporadic Creutzfeldt-Jakob disease in a previously healthy man in his 60s, who was infected with COVID-19 when the symptoms started.<ref>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7362815/ Creutzfeldt-Jakob disease in a man with COVID-19: SARS-CoV-2-accelerated neurodegeneration?] by Michael J. Young, Meabh O'Hare, Marcelo Matiello, and Jeremy D. Schmahmann, October 2020, ''PubMed''</ref> It was likely a coincidence, but it's possible that the mild brain damage caused by COVID-19 could have accelerated the disease.

===SARS-CoV-2 transmission by prions===
Multiple articles from reputable sources have used misleading wording to imply that SARS-CoV-2 uses prions to infect cells.<ref>[https://www.sciencedaily.com/releases/2020/08/200812161314.htm Researchers identify a protein that may help SARS-CoV-2 spread rapidly through cells] by Colorado State University, August 12, 2022, ''ScienceDaily''</ref><ref>[https://www.forbes.com/sites/jvchamary/2020/04/17/prion-like-coronavirus/?sh=25f7d9254680 Do Vampire-Like Proteins Make Coronavirus More Contagious?] by JV Chamary, April 17, 2020, ''Forbes''</ref> However, what was actually demonstrated was 'prion-like' proteins and prion-like domains. The only reasoning for the name is the fact that the N protein can change its folding to adapt to the host's cells. The name 'prion-like' is highly misleading. Prions do not change their folding to adapt to infect proteins. Prions are instead a misfolded version of a host protein, that cause other proteins to change shape. In addition, they generally only infect the same type of proteins that they are a variant of.{{citation needed}}

===mRNA vaccines cause Prion disease===
''See article [[COVID-19 denialism]] for more information''

In the tradition of anti-vaccine pseudoscience, there is a nonsensical claim that the COVID-19 vaccine causes Prion diseases such as vCJD. This idea is a revamp of the older idea that flu shots cause Alzheimer's Disease.<ref>[https://sciencebasedmedicine.org/can-mrna-based-covid-19-vaccines-cause-prion-disease/#:~:text=The%20abnormal%20folding%20of%20the%20prion%20proteins%20leads,shape%20onto%20normal%20variants%20of%20the%20same%20protein. Can mRNA-based COVID-19 vaccines cause prion disease or Alzheimer’s?] by David Gorski, February 22, 2021, ''Science Based Medicine''</ref> The newer version of the conspiracy is that Fetal Bovine Serum used in vaccines is contaminated with prion protein. This has never been confirmed in randomized clinical trials and no evidence of prion contamination in vaccines has ever been demonstrated. This is one of many pieces of dangerous anti-vaccine pseudoscience. Others who have suggested links include Stephanie Seneff,<ref>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9922164/ A Potential Role of the Spike Protein in Neurodegenerative Diseases: A Narrative Review] by Stephanie Seneff, Anthony M Kyriakopoulos, Greg Nigh, and Peter A McCullough, February 11, 2023 ''PubMed''</ref> and Kevin W. McCairn who suggested links between vaccines and amyloids along with prions.<ref>[https://m.youtube.com/watch?v=ww3UKBSGaH8 Spike Protein an Engineered Prion Protein? - Kevin McCairn PhD] by Vejon Health, February 4, 2024, ''YouTube''</ref>

==Treatments==

===Real treatments===
While no cure has been found for human prion diseases, there have been treatments that are able to extend the life of those affected.

====Quinacrine====
Quinacrine was one of the first non-quack treatments that showed promise. The drug was able to significantly slow the misfolding of PrP<sup>c</sup> to PrP<sup>Sc</sup> in prion-infected neuronal cells. While PrP<sup>Sc</sup> levels diminished in mice after treatment, their survival time was not increased. Clinical trials in humans showed no effect, likely because the treatment couldn't cross the blood-brain barrier. In addition, the treatment caused severe liver and kidney damage. The drug was retired.<ref>[https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1000673 Continuous Quinacrine Treatment Results in the Formation of Drug-Resistant Prions] by Sina Ghaemmaghami, Misol Ahn, Pierre Lessard, Kurt Giles, Giuseppe Legname, Stephen J. DeArmond, and Stanley B. Prusiner, November 26, 2009, ''Plos Pathogens''</ref>

====Antibodies====
Antibodies against PrP could be a promising treatment for TSEs. It could also translate to treatments for other prion diseases, such as Alzheimer's disease and Huntington's disease. Antibody treatments are not novel; drugs such as Humira and Herceptin are injected antibodies. An antibody called PRN100 was the first developed antibody to treat TSEs. It was able to completely cure prion-infected cells in a petri dish.  Mice were also cured, if treated during the early stages of the incubation period. If treated after becoming symptomatic, their survival time was tripled.<ref>[http://www.prionalliance.org/2014/02/04/what-are-the-potential-treatments-for-prion-disease/ What are the potential treatments for prion disease?] February 4, 2014, ''Prion Alliance''</ref> 6 patients have been treated with the antibody, but it wasn't successful. All of the patients died without any noticeable improvement in symptoms.{{Citation needed}}

====A more radical solution?====
No PrP<sup>c</sup> means no chance of misfolding into PrP<sup>Sc</sup>. This was demonstrated as early as 2003 in mice. Mice that had all their PrP removed while infected with a TSE were completely cured.<ref>[https://www.nature.com/news/2003/031027/full/news031027-10.html Gene tweak halts mad cow disease] by Tom Clarke, 31 October, 2023, ''Nature''</ref> Unfortunately, you can't just remove all PrP in a human; the mice were genetically modified with a genetic trigger that allowed the scientists to 'shut off' the PRNP gene. It's possible to eliminate the PRNP gene completely, and doing so causes the organism to be completely immune to TSEs.<ref>[>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2634447/ The Prion Protein Knockout Mouse] by Andrew D Steele, Susan Lindquist, and Adriano Aguzzi, April-June  2007, ''Prion'' ''PubMed''</ref> While this is farfetched at best in humans, it could be done to cows to allow for a complete immunity to bovine spongiform encephalopathy.<ref>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2813193/ Production of cattle lacking prion protein] by Jürgen A Richt, Poothappillai Kasinathan, Amir N Hamir, Joaquin Castilla, Thillai Sathiyaseelan, Francisco Vargas, Janaki Sathiyaseelan, Hua Wu, Hiroaki Matsushita, Julie Koster, Shinichiro Kato, Isao Ishida, Claudio Soto, James M Robl, and Yoshimi Kuroiwa</ref> This would allow for all parts of the animal to be used without danger, causing less damage to the environment, eliminating the potential for another BSE epidemic, and allowing cow farmers to make more money by using meat and bone meal and selling more parts of the cows. It's a win-win for everyone but the GMOphobes.

===Woo===
As with any deadly disease, there are [[quack]]s who promote [[woo]]. Earth Clinic, which is a natural health website, claims that [[apple cider vinegar]] and caprylic acid can treat the symptoms.<ref>[http://www.earthclinic.com/cures/mad_cow.html Mad Cow Disease Remedies] (Modified: Feb 17, 2017) ''Earth Clinic''.</ref> However, if someone ingests too much caprylic acid it may cause pain in the gastrointestinal tract. Caprylic acid is fairly safe if taken in small amounts; outside that it does nothing to help with symptoms.

==See also==
*[[Mad Cow Disease]]
*[[Medicine]]

==External links==
*[http://www.cdc.gov/prions/index.html CDC page on prions]
*[http://learn.genetics.utah.edu/content/molecules/prions/ University of Utah on prions]

==Notes==
<references group="note"/>

==References==
{{reflist|2|75%}}

[[Category:Disease]]
[[Category:Medicine]]
[[Category:Biology]]

Categories: Disease, Medicine, Biology