The good side of the prion: A molecule that is not only dangerous, but can help the brain grow

A few years ago it was found that certain proteins, the prions, when defective are dangerous, as they are involved in neurodegenerative syndromes such as the Creutzfeldt-Jakob and the Alzheimer diseases. But now research is showing their good side, too: when performing well, prions may be crucial in the development of the brain during childhood, as observed by a study carried out by a team of neuroscientists at Trieste’s SISSA which appeared yesterday in the Journal of Neuroscience.

Doctor Jekyll and Mr. Hyde: the metaphor of the good man who hides an evil side suits well the prion (PrPC in its physiological cellular form), a protein which abounds in our brain. Unlike Doctor Jekyll, the prion was at first considered for its upsetting properties: if the molecule abnormally folds over itself it unfortunately plays a crucial role in neurodegenerative processes that lead to dreadful syndromes such as the mad cow disease.

Prions, however, in their normal form abound in synapses, the contact points where the nervous signal is passed from a neuron to the next. Such protein relatively abounds in the brain of very young children, and this is the reason why scientists have assumed it may play a role in the
nervous system development, and in particular in neurogenesis, in the development of new synaptic connections and in plasticity.

More in detail

Maddalena Caiati, Victoria Safiulina, Sudhir Sivakumaran, Giuseppe Legname, Enrico Cherubini, all researchers at SISSA, and Giorgia Fattorini of the Università Politecnica delle Marche have verified at the molecular level the effects of PrPC on the cell plasticity of the hippocampus, a brain structure which has important functions related to memory. Maddalena Caiati and her colleagues have demonstrated that PrPC controls synaptic plasticity (the growth capacity of the nervous tissue) through a transduction pathway which involves also another protein, the protein kinase A enzyme (PKA). The recently published research is only the starting point. As for the future, it will be interesting to get a closer look at the role played by the prion protein in the development of neuronal circuits both under physiological and pathologic conditions in neurodegenerative diseases.

Identification of abnormal protein may help diagnose, treat ALS and frontotemporal dementia

Amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, and frontotemporal dementia (FTD) are devastating neurodegenerative diseases with no effective treatment. Researchers are beginning to recognize ALS and FTD as part of a spectrum disorder with overlapping symptoms. Now investigators reporting online February 12 in the Cell Press journal Neuron have discovered an abnormal protein that first forms as a result of genetic abnormalities and later builds up in the brains of many patients with either disease.

"In identifying the novel protein that abnormally accumulates in the brains of affected patients, we have uncovered a potentially new therapeutic target and biomarker that would allow clinicians to confirm diagnosis of the diseases," says senior author Dr. Leonard Petrucelli, Chair of Neuroscience at Mayo Clinic in Florida.

By analyzing brain tissue from patients with ALS or FTD, Dr. Petrucelli and his team discovered that the abnormal protein, which they call C9RANT, is generated as a result of repeat expansions of nucleotides in the noncoding region of the C9ORF72 gene. These expansions are the most common cause of ALS and FTD. “Simply put, an error in the highly regulated cellular process through which proteins are generated causes the abnormal production of C9RANT,” explains Dr. Petrucelli.

The researchers discovered the protein C9RANT after creating a novel antibody to specifically detect it. The ability to detect C9RANT in individuals’ cerebrospinal fluid may provide a valuable diagnostic and prognostic tool for identifying patients carrying the C9ORF72 repeat expansion and for then tracking the progression of the disease in these at-risk individuals.

"Although it remains to be shown whether C9RANT is causing the cell death or toxicity associated with disease symptoms, our discovery offers a potential target to prevent neuronal loss in patients carrying the C9ORF72 repeat expansion," says Dr. Petrucelli.

The concept that abnormal proteins accumulate and can be toxic to cells is not new. In fact, tau protein forms tangles in Alzheimer’s disease and alpha-synuclein forms clumps in Parkinson’s disease. Just as new therapies are being developed to break down the protein aggregates associated with these diseases, developing a therapeutic strategy to target C9RANT aggregates may also prove beneficial.

‘Robot’ cells answer call to arms

By thinking of cells as programmable robots, researchers at Rice University hope to someday direct how they grow into the tiny blood vessels that feed the brain and help people regain functions lost to stroke and disease.

Rice bioengineer Amina Qutub and her colleagues simulate patterns of microvasculature cell growth and compare the results with real networks grown in their lab. Eventually, they want to develop the ability to control the way these networks develop.

The results of a long study are the focus of a new paper in the Journal of Theoretical Biology.

“We want to be able to design particular capillary structures,” said Qutub, an assistant professor of bioengineering based at Rice’s BioScience Research Collaborative. “In our computer model, the cells are miniature adaptive robots that respond to each other, respond to their environment and pattern into unique structures that parallel what we see in the lab.”

When brain cells are deprived of oxygen – a condition called hypoxia that can lead to strokes – they pump out growth factor proteins that signal endothelial cells. Those cells, which line the interior of blood vessels, are prompted to branch off as capillaries in a process called angiogenesis to bring oxygen to starved neurons.

How these new vessels form networks and the shapes they take are of great interest to bioengineers who want to improve blood flow to parts of the brain by regenerating the microvasculature.

“The problem, especially as we age, is that we become less able to grow these blood vessels,” Qutub said. “At the same time, we’re at higher risk for strokes and neurodegenerative diseases. If we can understand how to guide the vessel structures and help them self-repair, we are a step closer to aiding treatment.”

What Causes Lou Gehrig’s Sticky Masses?

Globs of protein clustered in the neurons that control muscles have long been the hallmark of amyotrophic lateral sclerosis (ALS), the fatal neurodegenerative disease also commonly known as Lou Gehrig’s disease. Now, a study of the most commonly found mutant gene in people with ALS reveals an unexpected origin of some of those sticky masses, a finding that may offer drug developers a new target for treatments.

Located on the ninth chromosome, which explains part of its unwieldy name, the C9orf72 gene has a bit of a stutter. A typical version in healthy people contains a stretch of DNA where a string of six genetic letters—GGGGCC—repeats up to 25 times. Scientists have recently found that in a sizable share of people with ALS and frontotemporal dementia (FTD), a less common neurological disease characterized by language, memory, and emotional problems, this repeat occurs many more times; some people have thousands of copies.

Since these C9orf72 mutations were discovered in 2011, some researchers have speculated that the repeats interrupt production of the gene’s normal protein, which serves some as-yet unknown, but vital function in motor neurons or other brain cells. Others have hypothesized that the mutation spawns a large, misshapen strand of RNA that grabs on to proteins such as TDP-43, which normally help process RNA, creating protein tangles that starve the cell of the machinery it needs to function.

Molecular biologists at the Ludwig Maximilians University Munich in Germany and the University of Antwerp in Belgium, however, wondered whether the genetic stutters themselves coded for proteins that became tangled in the cell. Few scientists had considered this because the stutters don’t contain the “start signal” that allows proteins to be made. Still, in a few other diseases caused by genetic repeats, the cell manages to produce proteins from the abnormal gene despite lacking this signal. Sometimes these proteins are toxic and ultimately kill the cell.

Based on the DNA sequence of the GGGGCC-laden C9orf72 seen in ALS and FTD patients, the European team determined that if translated, the gene would produce various proteins containing strings of repeat amino acids. Dubbed dipeptide repeat (DPR) proteins, these molecules don’t normally appear in humans and should be prone to clumping, the scientists concluded. Indeed, when they began to search for DPR protein clusters in actual human brain tissues, they found them in tissue from FTD and ALS patients with the C9orf72 mutation. No such lumps showed up in the brain tissue of healthy controls or ALS and FTD patients without the C9orf72 mutation, increasing the likelihood that the mutation produced them, Dieter Edbauer, a molecular biologist at Ludwig Maximilians, and his co-authors report online today in Science.

Translation error tracked in the brain of dementia patients

In certain dementias silent areas of the genetic code are translated into highly unusual proteins by mistake. An international team of scientists including researchers from the German Center for Neurodegenerative Diseases (DZNE) in Munich and the Ludwig-Maximilians-Universität (LMU) present this finding in the online edition of “Science”. The proteins that have now been identified shouldn’t actually exist. Nevertheless, they build the core of cellular aggregates whose identity has been enigmatic until now. These aggregates are typically associated with hereditary neurodegenerative diseases including variants of frontotemporal dementia (FTD), also known as frontotemporal lobar degeneration (FTLD), and amyotrophic lateral sclerosis (ALS). They are likely to be damaging and might be a target for therapy.

FTD and ALS are part of a group of neurodegenerative diseases that show a broad and overlapping variety of symptoms: Patients often suffer from dementia, personality changes and may also be affected by language abnormalities and movement disorders. The problems often arise before the age of 65 without a clear cause. However, about 30 percent of cases are linked to a genetic cause. In Europe approximately 10 percent of patients show a common genetic feature: In their DNA (the carrier of the genetic code) a particular short sequence appears in numerous copies one after another. Furthermore, proteins of unknown identity accumulate inside the brain of these patients. As it turns out both findings are directly related – that is what the team of researchers including molecular biologists Dieter Edbauer and Christian Haass has now been able to show.

“We have found that the proteins are linked to a genetic peculiarity which many patients have in common. At a certain location inside the gene C9orf72 there are several hundred repeats of the sequence GGGGCC, while healthy people display less than 20 such copies,” explains Prof. Edbauer, who researches at the DZNE and the LMU. “But it is surprising that these proteins are actually made, because these repeats fall into a region of the DNA that should not be translated into proteins.”

An area of DNA assumed to be silent

The DNA holds the blueprints for building proteins. In general, the beginning of such a blueprint is indicated by a certain molecular start signal, but the usual signal is missing in this case. The region of DNA comprising the numerous repeats should therefore not be translated into proteins. It seems that the process of protein synthesis is initiated in a non-textbook way. “Although quite rare there are two known alternatives to the common mechanism. Which procedure applies here, we don’t know yet,” says Prof. Haass, Site Speaker of the DZNE in Munich and chair of Metabolic Biochemistry at LMU.

Nevertheless, in cell culture experiments the researchers were able to show that long repeats of the sequence GGGGCC may in fact lead to the production of proteins, even though the usual start signal is missing. Furthermore, they identified the same proteins in the particles that typically accumulate in the brain of patients. The scientist could also identify their composition: They turned out to be dipeptid-repeat proteins, which comprise a very large number of identical building blocks.

“These are very extraordinary proteins that usually don’t show-up in the organism,” Edbauer notes. “As far as we know, they are completely useless and scarcely soluble. Therefore, they tend to aggregate and seem to damage the nerve cells. We haven’t formally proven toxicity, but there is ample evidence.” Because of their peculiarity these proteins might be an interesting target for new therapies. “As the mechanism of their production is so unusual, we may find ways to inhibit their synthesis without interfering with the formation of other proteins. One could also try to block their aggregation and accelerate their decomposition.”

The scientists have applied for a patent and are pursuing a major goal. “At the DZNE in Munich it is our dream to develop a therapy against these devastating diseases,“ Haass and Edbauer conclude.

Study Confirms No Transmission of Alzheimer’s Proteins Between Humans

Mounting evidence demonstrates that the pathological proteins linked to the onset and progression of neurodegenerative disorders are capable of spreading from cell-to-cell within the brains of affected individuals and thereby “spread” disease from one interconnected brain region to another. A new study found no evidence to support concerns that these abnormal disease proteins are “infectious” or transmitted from animals to humans or from one person to another. The study by researchers from the Perelman School of Medicine at the University of Pennsylvania, in conjunction with experts from the U.S. Centers for Disease Control and the Department of Health and Human Services, appears online in JAMA Neurology.

Cell-to-cell transmission is a potentially common pathway for disease spreading and progression in diseases like Alzheimer’s (AD) and Parkinson’s (PD) disease as well as frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS) and other related disorders. It appears that misfolded proteins spread from one cell to another and that the affected neurons become dysfunctional, while these toxic proteins go on to damage other regions of the brain over time.

"By interrogating an existing database with information on a cohort of well-characterized patients, we were able to determine that there is no evidence suggesting the pathology of Alzheimer’s or Parkinson’s can transmit between humans,"  said senior author John Q. Trojanowski, MD, PhD, professor of Pathology and Laboratory Medicine and co-director of the Penn Center for Neurodegenerative Disease Research. "We can now redouble efforts to find treatments, via immunotherapies or other approaches to stop the spreading of these toxic proteins between cells."

In order to verify whether such proteins could potentially be carried from person to person, the team of researchers analyzed data from an existing cohort of patients who had received human growth hormone (hGH) from cadaveric pituitary glands via a national program, as a beneficial treatment for stunted growth, before synthetic hGH was available. Nearly 7,700 patients were treated with cadaver-derived hGH (c-hGH) in the US between 1963 and 1985. In the mid-1980s, more than 200 patients worldwide who had received c-hGH inadvertently contaminated with prion proteins from affected donor pituitary tissue went on to develop an acquired form of Creutzfeldt-Jakob disease (CJD), a rare, degenerative, invariably fatal brain disorder caused by pathological prion proteins that also are the cause of Mad Cow disease. Since then, the cohort has been followed to track any additional cases of CJD, with extensive medical histories for patients over the 30+ years since the c-hGH therapy was stopped after the link to CJD was discovered in 1985.

Chemical reaction keeps stroke-damaged brain from repairing itself

Nitric oxide, a gaseous molecule produced in the brain, can damage neurons. When the brain produces too much nitric oxide, it contributes to the severity and progression of stroke and neurodegenerative diseases such as Alzheimer’s. Researchers at Sanford-Burnham Medical Research Institute recently discovered that nitric oxide not only damages neurons, it also shuts down the brain’s repair mechanisms. Their study was published by the Proceedings of the National Academy of Sciences the week of February 4.

“In this study, we’ve uncovered new clues as to how natural chemical reactions in the brain can contribute to brain damage—loss of memory and cognitive function—in a number of diseases,” said Stuart A. Lipton, M.D., Ph.D., director of Sanford-Burnham’s Del E. Webb Neuroscience, Aging, and Stem Cell Research Center and a clinical neurologist.

Lipton led the study, along with Sanford-Burnham’s Tomohiro Nakamura, Ph.D., who added that these new molecular clues are important because “we might be able to develop a new strategy for treating stroke and other disorders if we can find a way to reverse nitric oxide’s effect on a particular enzyme in nerve cells.”

Nitric oxide inhibits the neuroprotective ERK1/2 signaling pathway

Learning and memory are in part controlled by NMDA-type glutamate receptors in the brain. These receptors are linked to pores in the nerve cell membrane that regulate the flow of calcium and sodium in and out of the nerve cells. When these NMDA receptors get over-activated, they trigger the production of nitric oxide. In turn, nitric oxide attaches to other proteins via a reaction called S-nitrosylation, which was first discovered by Lipton and colleagues. When those S-nitrosylated proteins are involved in cell survival and lifespan, nitric oxide can cause brain cells to die prematurely—a hallmark of neurodegenerative disease.

In their latest study, Lipton, Nakamura and colleagues used cultured neurons as well as a living mouse model of stroke to explore nitric oxide’s relationship with proteins that help repair neuronal damage. They found that nitric oxide reacts with the enzyme SHP-2 to inhibit a protective cascade of molecular events known as the ERK1/2 signaling pathway. Thus, nitric oxide not only damages neurons, it also blocks the brain’s ability to self-repair.

Kynurenines in the CNS: recent advances and new questions

Various pathologies of the central nervous system (CNS) are accompanied by alterations in tryptophan metabolism. The main metabolic route of tryptophan degradation is the kynurenine pathway; its metabolites are responsible for a broad spectrum of effects, including the endogenous regulation of neuronal excitability and the initiation of immune tolerance. This Review highlights the involvement of the kynurenine system in the pathology of neurodegenerative disorders, pain syndromes and autoimmune diseases through a detailed discussion of its potential implications in Huntington’s disease, migraine and multiple sclerosis. The most effective preclinical drug candidates are discussed and attention is paid to currently under-investigated roles of the kynurenine pathway in the CNS, where modulation of kynurenine metabolism might be of therapeutic value.

A better way to culture central nervous cells

A protein associated with neuron damage in people with Alzheimer’s disease is surprisingly useful in promoting neuron growth in the lab, according to a new study by engineering researchers at Brown University. The findings, in press at the journal Biomaterials, suggest a better method of growing neurons outside the body that might then be implanted to treat people with neurodegenerative diseases.

The research compared the effects of two proteins that can be used as an artificial scaffold for growing neurons (nerve cells) from the central nervous system. The study found that central nervous system neurons from rats cultured in apolipoprotein E-4 (apoE4) grew better than neurons cultured in laminin, which had been considered the gold standard for growing mammalian neurons in the lab.

“Most scientists assumed that laminin was the best protein for growing CNS (central nervous system),” said Kwang-Min Kim, a biomedical engineering graduate student at Brown University and lead author of the study, “but we demonstrated that apoE4 has substantially better performance for mammalian CNS neurons.”

Kim performed the research under the direction of Tayhas Palmore, professor of engineering and medical science and Kim’s Ph.D. adviser. Also involved in the project was Janice Vicenty, an undergraduate from the University of Puerto Rico, who was working in the Palmore lab as a summer research fellow through the Leadership Alliance.

The results are surprising partly because of the association of apoE4 with Alzheimer’s. Apolipoproteins are responsible for distributing and depositing cholesterols and other lipids in the brain. They come in three varieties: apoE2, apoE3 and apoE4. People with the gene that produces apoE4 are at higher risk for amyloid plaques and neurofibrillary tangles, the hallmarks of Alzheimer’s. But exactly how the protein itself contributes to Alzheimer’s is not known.

This study suggests that outside the body, where the protein can be separated from the cholesterols it normally carries, apoE4 is actually beneficial in promoting neuron growth.