Posts tagged prion proteins
Articles and news from the latest research reports.
Image: A. Amyloid-beta plaques in Alzheimers B. Neurofibrillary tangles (tau) in Alzheimer’s C. Lewy bodies (alpha-synuclein) in Parkinson’s D. TDP-43 inclusions in motor neurons in ALS
Prion-like proteins drive several diseases of aging
Two leading neurology researchers have proposed a theory that could unify scientists’ thinking about several neurodegenerative diseases and suggest therapeutic strategies to combat them.
The theory and backing for it are described in the September 5, 2013 issue of Nature.
Mathias Jucker and Lary Walker outline the emerging concept that many of the brain diseases associated with aging, such as Alzheimer’s and Parkinson’s, are caused by specific proteins that misfold and aggregate into harmful seeds. These seeds behave very much like the pathogenic agents known as prions, which cause mad cow disease, chronic wasting disease in deer, scrapie in sheep, and Creutzfeldt-Jakob disease in humans.
Walker is research professor at Yerkes National Primate Research Center, Emory University. Jucker is head of the Department of Cellular Neurology at the Hertie Institute for Clinical Brain Research at the University of Tübingen and the German Center for Neurodegenerative Diseases.
Unlike prion diseases, which can be infectious, Alzheimer’s, Parkinson’s, and other neurodegenerative diseases can not be passed from person to person under normal circumstances. Once all of these diseases take hold in the brain, however, it is increasingly apparent that the clumps of misfolded proteins spread throughout the nervous system and disrupt its function.
The authors were the first to show that a protein that is involved in Alzheimer’s disease – known as amyloid-beta – forms prion-like seeds that stimulate the aggregation of other amyloid-beta molecules in senile plaques and in brain blood vessels. Since then, a growing number of laboratories worldwide have discovered that proteins linked to other neurodegenerative disorders also share key features with prions.
Age-related neurodegenerative disorders remain stubbornly resistant to the discovery of effective treatments. Jucker and Walker propose that the concept of pathogenic protein seeding not only could focus research strategies for these seemingly unrelated diseases, but it also suggests that therapeutic approaches designed to thwart prion-like seeds early in the disease process could eventually delay or even prevent the diseases.
Alzheimer’s missing link found: Is a promising target for new drugs
Yale School of Medicine researchers have discovered a protein that is the missing link in the complicated chain of events that lead to Alzheimer’s disease, they report in the Sept. 4 issue of the journal Neuron. Researchers also found that blocking the protein with an existing drug can restore memory in mice with brain damage that mimics the disease.
“What is very exciting is that of all the links in this molecular chain, this is the protein that may be most easily targeted by drugs,” said Stephen Strittmatter, the Vincent Coates Professor of Neurology and senior author of the study. “This gives us strong hope that we can find a drug that will work to lessen the burden of Alzheimer’s.”
Scientists have already provided a partial molecular map of how Alzheimer’s disease destroys brain cells. In earlier work, Strittmatter’s lab showed that the amyloid-beta peptides, which are a hallmark of Alzheimer’s, couple with prion proteins on the surface of neurons. By an unknown process, the coupling activates a molecular messenger within the cell called Fyn.
In the Neuron paper, the Yale team reveals the missing link in the chain, a protein within the cell membrane called metabotropic glutamate receptor 5 or mGluR5. When the protein is blocked by a drug similar to one being developed for Fragile X syndrome, the deficits in memory, learning, and synapse density were restored in a mouse model of Alzheimer’s.
Strittmatter stressed that new drugs may have to be designed to precisely target the amyloid-prion disruption of mGluR5 in human cases of Alzheimer’s and said his lab is exploring new ways to achieve this.
New models advance the study of deadly human prion diseases
By directly manipulating a portion of the prion protein-coding gene, Whitehead Institute researchers have created mouse models of two neurodegenerative diseases that are fatal in humans. The highly accurate reproduction of disease pathology seen with these models should advance the study of these unusual but deadly diseases.
“By altering single amino acid codons in the gene coding for the prion protein, in the natural context of the genome—no over expression or other artificial manipulations—we can produce completely different neurodegenerative diseases, each of which spontaneously generates an infectious prion agent,” says Whitehead Member Susan Lindquist. “The work irrefutably establishes the prion hypothesis.”
According to the prion hypothesis, prion proteins infect by passing along their misfolded shape in templated fashion, unlike viruses or bacteria, which depend on DNA or RNA to transmit their information. Certain changes to the prion protein (PrP) create a misshapen structure, which is replicated by contact. The misfolded proteins accumulate, creating clumps that are toxic to surrounding tissue.
PrP is expressed at high levels in the brain, and prion diseases, including Creutzfeldt-Jakob disease (CJD) in humans, bovine spongiform encephalopathy (BSE, or “mad cow disease”) in cows, and scrapie in sheep, wreak havoc on the brain and other neural tissues. Some prion diseases, like BSE, can be transmitted from feed animals to humans.
The study of these highly unusual but devastating prion diseases has to date been thwarted by a lack of animal models that faithfully mimic the disease processes in humans. However, Walker Jackson, a former postdoctoral researcher in Lindquist’s lab is changing that, creating novel mouse models of human fatal familial insomnia (FFI) and CJD. His research is reported online this week in the Proceedings of the National Academy of Sciences (PNAS).
To generate the models, Jackson created two mutated versions of the PrP-coding gene by changing a single codon—one of the three-nucleotide “words” in genes that code for the various amino acids in proteins. One mutation is known to cause FFI, while the other induces CJD. Unlike previous models that randomly inserted the mutations into the genome, occasionally increasing PrP expression, Jackson’s models faithfully mimic the human disease—from as to disease onset, to PrP production, to infectiousness. In the brain, his FFI mice develop neuronal loss in the thalamus and his CJD mice experience spongiosis in the hippocampus and the cerebellum, reflecting the damage seen in the brains of human patients.
“Walker (Jackson)’s work provides two extraordinary models of neurodegeneration,” says Lindquist, who is also a professor of biology at MIT. “Most mouse models produce pathology that only distantly resembles human diseases. These nail it, for two of the most enigmatic human diseases in the world.”
With the FFI and CJD models in hand, Jackson says he’s excited to investigate how the pathology of these diseases develops.
“Now we have two interesting models that are selectively targeting specific parts of the brain: the thalamus in FFI and the hippocampus in CJD,” says Jackson, who is now a Group Leader at the German Center for Neurodegenerative Disease. “But instead of focusing on areas that are heavily affected by the disease, we’ll be looking at the areas that seem to be resisting the disease to see what they’re doing. The protein is there, but for some reason, it’s not toxic.”
Initial characterization of one of the models (for FFI) was reporter earlier in Neuron.
Normal prion protein regulates iron metabolism
An iron imbalance caused by prion proteins collecting in the brain is a likely cause of cell death in Creutzfeldt-Jakob disease (CJD), researchers at Case Western Reserve University School of Medicine have found.
The breakthrough follows discoveries that certain proteins found in the brains of Alzheimer’s and Parkinson’s patients also regulate iron. The results suggest that neurotoxicity by the form of iron, called redox-active iron, may be a trait of neurodegenerative conditions in all three diseases, the researchers say.
Further, the role of the normal prion protein known as PrPc in iron metabolism may provide a target for strategies to maintain iron balance and reduce iron-induced neurotoxicity in patients suffering from CJD, a rare degenerative disease for which no cure yet exists.
The researchers report that lack of PrPC hampers iron uptake and storage and more findings are now in the online edition of the Journal of Alzheimer’s Disease.
"There are many skeptics who think iron is a bystander or end-product of neuronal death and has no role to play in neurodegenerative conditions," said Neena Singh, a professor of pathology and neurology at Case Western Reserve and the paper’s senior author. "We’re not saying that iron imbalance is the only cause, but failure to maintain stable levels of iron in the brain appears to contribute significantly to neuronal death."
Prions are misfolded forms of PrPC that are infectious and disease-causing agents of CJD. PrPc is the normal form present in all tissues including the brain. PrPc acts as a ferrireductase, that is, it helps to convert oxidized iron to a form that can be taken up and utilized by the cells, the scientists show.
In their investigation, mouse models that lacked PrPC were iron-deficient. By supplementing their diets with excess inorganic iron, normal levels of iron in the body were restored. When the supplements stopped, the mice returned to being iron-deficient.
Examination of iron metabolism pathways showed that the lack of PrPC impaired iron uptake and storage, and alternate mechanisms of iron uptake failed to compensate for the deficiency.
Cells have a tight regulatory system for iron uptake, storage and release. PrPC is an essential element in this process, and its aggregation in CJD possibly results in an environment of iron imbalance that is damaging to neuronal cells, Singh explained
It is likely that as CJD progresses and PrPC forms insoluble aggregates, loss of ferrireductase function combined with sequestration of iron in prion aggregates leads to insufficiency of iron in diseased brains, creating a potentially toxic environment, as reported earlier by this group and featured in Nature Journal club.
Recently, members of the Singh research team also helped to identify a highly accurate test to confirm the presence of CJD in living sufferers. They found that iron imbalance in the brain is reflected as a specific change in the levels of iron-management proteins other than PrPc in the cerebrospinal fluid. The fluid can be tapped to diagnose the disease with 88.9 percent accuracy, the researchers reported in the journal Antioxidants & Redox Signaling online last month.
Singh’ s team is now investigating how prion protein functions to convert oxidized iron to a usable form. They are also evaluating the role of prion protein in brain iron metabolism, and whether the iron imbalance observed in cases of CJD, Alzheimer’s disease and Parkinson’s disease is reflected in the cerebrospinal fluid. A specific change in the fluid could provide a disease-specific diagnostic test for these disorders.
(Source: eurekalert.org)