Altered protein found to cause rare Parkinson’s-like disease 
 
 Photo: Mati Image 1 of / 1 Caption Close Image 1 of 1 Dr. Stanley Prusiner, a scientist at the Medical School of the University of California at San Francisco who discovered the "mad cow disease," delivers a speech after receiving from Israeli President Ezer Weitzman the Wolf Prize honoring his research during a ceremony at the Knesset in Jerusalem Sunday, March 25, 1996. Over the past two decades, a team led by Prusiner has discovered and studied the disease-causing form of prion proteins that cause mad cow disease. Researchers at his institute on the Mission Bay campus announced Monday, Aug. 31, 2015, the discovery of a new form of prion linked to a rare Parkinson’s-like disease called Multiple System Atrophy. AP PHOTO 3/24/96. less Dr. Stanley Prusiner, a scientist at the Medical School of the University of California at San Francisco who discovered the "mad cow disease," delivers a speech after receiving from Israeli President Ezer ... more Photo: Mati Altered protein found to cause rare Parkinson’s-like disease 1 / 1 Back to Gallery 
 
 When Stanley B. Prusiner, a UCSF neurologist, first proposed that inert proteins he called prions could somehow fold into strange shapes and infect humans with rare diseases of the brain, his idea 30 years ago was widely dismissed as nonsense. 
 
 His critics were wrong. 
 
 Twenty years later, those infectious prions — which Prusiner coined from two words, protein and infection — won him a Nobel Prize, and today his Institute for Neurodegenerative Disease has its own building on the medical center’s Mission Bay campus. It’s a scientific hive where researchers, lab technicians and medical students labor to understand the many disorders that endanger the human brain and the nervous system. 
 
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 Now Kurt Giles, a British-born neurologist at the UCSF Institute, is reporting that he and his colleagues have found that a new type of prion is the direct cause of a rare and fatal brain disorder whose symptoms are similar to Parkinson’s disease. 
 
 Their discovery adds new evidence that varied types of the once-disdained prions might be involved in causing other fatal brain disorders like Parkinson’s, as well as Alzheimer’s disease, Giles and Prusiner suggest. 
 
 In a report published Monday in the Proceedings of the National Academy of Sciences, Giles and an international group of colleagues conclude that their newly discovered type of misfolded prion, called alpha-synuclein, causes a rare disease named multiple-system atrophy, known as MSA. Around the world, the brain disorder affects only 3 out of 100,000 people, all older than 50. It is incurable and inevitably fatal. 
 
 To prove their point, Giles and colleagues in the U.S., Britain and Australia took tissue samples containing prions from the brains of people who had died of MSA. And in experiment after experiment, the researchers found evidence that the prions then transmitted the infection to laboratory cultures of human and mouse tissue. The prions in bits of tissue also transmitted the disease to living laboratory mice. And, in still more experiments, the newly infected mouse tissue samples also spread the disease to other living mice, they found. 
 
 “It’s quite clear that this is the first new type of prion to be discovered in the last 50 years, and that it clearly causes MSA,” Giles said. 
 
 When Prusiner first reported the existence of the strange proteins he called prions in 1982, he found they were the cause of the rare and fatal human disorder called Creutzfeldt-Jakob disease, or CJD, and that claim is now widely recognized. The same prions were also found to cause animal diseases like scrapie in sheep and bovine spongiform encephalopathy, better known as mad cow disease, in cattle. 
 
 About 300 people in the U.S. die of CJD every year, according to the National Institute of Neurological Disorders and Stroke. The symptoms occur at about age 60, and about 90 percent of people who get the disease die within a year. The early symptoms are often similar to patients with Parkinson’s disease. 
 
 Prion proteins exist in two shapes, and the normally shaped prions found throughout the bodies of humans and animals are harmless. But when they fold into new shapes — “misfolded,” scientists call them — they become infectious, like viruses. At the same time, those same misfolded prions can cause normal prions to become misshapen, and they become infectious as well, Prusiner said. 
 
 As prion research at the institute continues, it is becoming increasingly clear that different misfolded prions will turn out to be involved in causing both Parkinson’s and Alzheimer’s diseases, Prusiner said. But the proof is yet to come. 
 
 David Perlman is The San Francisco Chronicle’s science editor. E-mail: dperlman@sfchronicle.com Twitter: @daveperlman 

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 A rare, incurable brain disorder that resembles Parkinson’s disease is caused by a misfolded brain protein called a prion, similar to the prions that cause mad cow disease, researchers reported on Monday. 
 
 The discovery adds to a very short list of human diseases linked to mutant prions, and suggests anyone doing brain surgery should take extra care, the researchers said. 
 
 The disease is called multiple system atrophy or MSA, and it affects somewhere between 15,000 and 50,000 Americans at any given time. 
 
 “Symptoms tend to appear in a person’s 50s and advance rapidly over the course of 5 to 10 years, with progressive loss of motor function and eventual confinement to bed,” the National Institute for Neurological Disorders and Stroke, part of the National Institutes of Health, says on its website. 
 
 “Now we’ve conclusively shown that a new type of prion causes MSA." 
 
 “People with MSA often develop pneumonia in the later stages of the disease and may suddenly die from cardiac or respiratory issues.” 
 
 There’s no cure, and MSA can often be confused for Parkinson’s disease. 
 
 Dr. Stanley Prusiner of the University of California San Francisco and colleagues wanted to see if it might be caused by a prion, similar to the misfolded prions that cause Creutzfeldt Jakob Disease (CJD); a relative in cattle called bovine spongiform encephalopathy or BSE; and a variant of CJD (vCJD) that has been linked to eating cattle affected by BSE. 
 
 Prusiner won the 1997 Nobel Prize in Medicine for his discovery of prions. They spread disease by touching other brain proteins and causing them to malfunction. 
 
 He and his team started with the brains of 14 people who had died with MSA. It can only be definitively diagnosed by examining the brain after death, and is marked by the inappropriate buildup of a protein called alpha synuclein. 
 
 Prions from their brains infected cells in lab dishes, changing their function, and caused symptoms resembling Parkinson’s in mice, they reported in the Proceedings of the National Academies of Science. 
 
 They examined the brains of the mice and found a buildup of alpha-synuclein. 
 
 “Now we’ve conclusively shown that a new type of prion causes MSA,” said Kurt Giles, a neurology expert at UCSF who worked on the study. 
 
 This doesn’t necessarily mean that MSA is transmissible in the same way that CJD and BSE can be, outside experts cautioned. 
 
 “It is important to state that this study does not demonstrate human-to-human transmission. In fact, it suggests MSA does not transmit easily,” Dr. Valerie Sim, a prion expert at the University of Alberta in Canada, said in a statement. 
 
 Cattle got BSE from eating sheep infected with scrapie, a similar brain condition. People can get vCJD from eating infected beef but it is extremely rare – just over 200 cases worldwide have been reported since the first case in the mid-1990s. Cannibals who eat human brains get a similar disease called kuru, and deer and elk are vulnerable to a condition called chronic wasting disease. 
 
 “It is important to state that this study does not demonstrate human-to-human transmission." 
 
 Knowing there’s another disease spread by prions is worrying because it is extremely difficult to destroy the mutant prions. Standard disinfection does not remove them, and people have been infected with CJD from contaminated surgical instruments. 
 
 “You can’t kill a protein,” Giles said. “And it can stick tightly to stainless steel, even when the surgical instrument is cleaned.” 
 
 Some experimental therapies for Parkinson’s involve implanting cells or electrodes into the brain, and because MSA can be confused for Parkinson’s, surgeons should take extra care, the researchers said. 
 
 There’s also a theory that has yet to be proved that Parkinson’s might be caused by mutant prions, Prusiner’s team noted. 
 
 And, they said, their findings show that MSA is distinct from Parkinson’s. Sometimes doctors try the standard Parkinson’s treatment levodopa in MSA patients. This study suggests researchers need to take a new approach. 
 
 However, there’s no known treatment for any of the prion diseases, including BSE and CJD. 

 Prions are proteins that assume alternate shapes that become self-propagating, and while some prions perform normal physiological functions, others cause disease. Prions were discovered while studying the cause of rare neurodegenerative diseases of animals and humans called scrapie and Creutzfeldt–Jakob disease, respectively. We report here the discovery of α-synuclein prions that cause a more common neurodegenerative disease in humans called multiple system atrophy (MSA). In contrast to MSA, brain extracts from Parkinson’s disease (PD) patients were not transmissible to genetically engineered cells or mice, although much evidence argues that PD is also caused by α-synuclein, suggesting that this strain (or variant) is different from those that cause MSA. 
 
 Abstract 
 
 Prions are proteins that adopt alternative conformations that become self-propagating; the PrPSc prion causes the rare human disorder Creutzfeldt–Jakob disease (CJD). We report here that multiple system atrophy (MSA) is caused by a different human prion composed of the α-synuclein protein. MSA is a slowly evolving disorder characterized by progressive loss of autonomic nervous system function and often signs of parkinsonism; the neuropathological hallmark of MSA is glial cytoplasmic inclusions consisting of filaments of α-synuclein. To determine whether human α-synuclein forms prions, we examined 14 human brain homogenates for transmission to cultured human embryonic kidney (HEK) cells expressing full-length, mutant human α-synuclein fused to yellow fluorescent protein (α-syn140*A53T–YFP) and TgM83+/− mice expressing α-synuclein (A53T). The TgM83+/− mice that were hemizygous for the mutant transgene did not develop spontaneous illness; in contrast, the TgM83+/+ mice that were homozygous developed neurological dysfunction. Brain extracts from 14 MSA cases all transmitted neurodegeneration to TgM83+/− mice after incubation periods of ∼120 d, which was accompanied by deposition of α-synuclein within neuronal cell bodies and axons. All of the MSA extracts also induced aggregation of α-syn*A53T–YFP in cultured cells, whereas none of six Parkinson’s disease (PD) extracts or a control sample did so. Our findings argue that MSA is caused by a unique strain of α-synuclein prions, which is different from the putative prions causing PD and from those causing spontaneous neurodegeneration in TgM83+/+ mice. Remarkably, α-synuclein is the first new human prion to be identified, to our knowledge, since the discovery a half century ago that CJD was transmissible. 

 Scientists Discover New Disease Caused By Prion Protein 
 
 Scientists have discovered the first new human disease caused by a "prion" in more than 50 years. Prions are strange, deformed proteins that can act like viruses and bacteria. 
 
 ROBERT SIEGEL, HOST: 
 
 Scientists have discovered a mutant protein that can spread through the brain like a virus, causing a rare and terrible disease. NPR health correspondent Rob Stein reports that the findings could be an important advance for many brain disorders, including Parkinson's and Alzheimer's. 
 
 ROB STEIN, BYLINE: Fifty years ago, scientists made a stunning discovery. Bizarre, deformed proteins called prions could spread sort of like viruses and bacteria and cause awful brain diseases. Thankfully, these diseases are pretty rare and hard to get, like kuru, which cannibals in Papua New Guinea got from eating human brains and mad cow disease, which people can get from eating infected cow brains. But Kurt Giles says scientists thought there could be more of these diseases. 
 
 KURT GILES: There's been, the past 10 years now, but really, more so maybe the past five years, the understanding that many neurodegenerative diseases may be prion diseases. 
 
 STEIN: Diseases like Alzheimer's and Parkinson's, so Giles and his colleagues at the University of California, San Francisco took a look at a disease called multiple-system atrophy or MSA. 
 
 GILES: Initially, it looks like Parkinson's disease. People have the tremors and the loads of problems of Parkinson's disease. 
 
 STEIN: But MSA destroys the brain even faster than Parkinson's. Giles and his colleagues suspected MSA might be caused by a misshapen version of a protein called alpha-synuclein. So they created mice that have the human form of that protein in their brains and injected the mice with alpha-synuclein from the brains of 14 people who had died from MSA. 
 
 GILES: And in every case, the mice died about four months later of the disease. 
 
 STEIN: Under a microscope, their brains looked exactly like the brains of people who died from MSA. And tissue taken from the brains of the dead mice could do the same thing to the brains of other mice. 
 
 GILES: So that really shows that this is a transmissible disease and that the protein involved in it is acting as a prion. 
 
 STEIN: That has all kinds of implications. For starters, Giles says it raises the disturbing possibility that MSA could spread from one person to another by surgical instruments that have been used on the brains of MSA patients. 
 
 GILES: Protein sticks very tightly to the stainless steel. And when you clean it afterwards, you could potentially still have misfolded clumps of protein on the surgical instruments that, if you then do surgery on a second person, could potentially induce that in the other person. 
 
 STEIN: And the new research, which is being published in the proceedings of the National Academy of Sciences, could be really important for other reasons. 
 
 CORINNE LASMEZAS: The fact that these proteins behave like prions - it has tremendous implications. 
 
 STEIN: Corinne Lasmezas is a neuroscientist at the Scripps Research Institute in Florida. If a prion can cause MSA, Lasmezas says that's a big boost for the idea that prions could cause other much more common diseases like Alzheimer's, Parkinson's and Lou Gehrig's disease. 
 
 LASMEZAS: It's one more stone in our garden of knowledge now about what these toxic proteins are doing. And we know that this is where we have to intervene in order to be able to treat these diseases. 
 
 STEIN: Scientists are already trying to find drugs that block these mutant proteins in the hopes of finally finding something that could treat people suffering from MSA, Alzheimer's, Parkinson's and other terrible brain diseases. Rob Stein, NPR News. 
 
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– Multiple system atrophy, or MSA, is a rare and horrible disease that will destroy your brain and inevitably kill you, and the study of it has now yielded a major breakthrough in our understanding of brain diseases. Researchers have discovered that MSA is caused by a prion, a kind of deformed protein that spreads like a virus and is known to cause Creutzfeldt-Jakob disease in humans and bovine spongiform encephalopathy (aka mad cow disease) in cattle, reports the San Francisco Chronicle. The University of California, San Francisco scientists say alpha-synuclein is the first new kind of prion to be identified "since the discovery a half century ago that CJD was transmissible," they write in Proceedings of the National Academy of Sciences. The scientists injected alpha-synuclein taken from the brains of 14 people who died from MSA into mice; NPR reports the animals were dead within about four months, and the dead creatures' brains "looked exactly like" those of the humans killed by MSA. The find lends support to the idea that "misfolded" prions could be behind more common brain diseases like Parkinson's and Alzheimer's. No cure currently exists for prion-caused diseases, which are generally spread by eating brains or eating animals that have eaten brains. But the find could help fight MSA, which acts like a more aggressive version of Parkinson's and affects up to 50,000 Americans at any time, NBC News reports. And while one prion expert says the research "suggests MSA does not transmit easily," study author Kurt Giles says "protein sticks very tightly to the stainless steel" and standard disinfecting may not kill prions, meaning it's possible MSA could be spread by contaminated surgical instruments. (Eating brains nearly wiped out this tribe in Papua New Guinea.)