Low Levels of Toxic Proteins Linked to Brain Diseases: Research

Scientists studying thread-like chains of protein - called amyloid fibres - have found that low levels of these proteins may cause more harm to health than high levels.

These rarely formed protein chains, which have been linked with dozens of diseases, are produced as a result of a genetic flaw or changes in body chemistry brought about by ageing.

When this happens, short fibres are formed which become sticky and attract copies of themselves, forming an endless chain. These chains spontaneously break, creating more filament ends to which more proteins attach.

In the context of neurodegenerative diseases, it is these short, broken pieces that seem to be most harmful, scientists say.

Researchers have found that when protein levels are low, lots of short protein threads are formed. But when protein levels are high, this spontaneous breakage stops and most protein filaments remain long.

Compared with harmful short protein fibres, long fibres do not appear to be damaging in the case of neurodegenerative diseases. Researchers therefore believe that high levels of the protein - which lead to these longer chains - may actually be protective.

In addition to shedding light on disease, this insight into the protein chains may help scientists develop useful biomaterials, such as cell scaffolds, which are used for tissue engineering or to make artificial silk.

Cait MacPhee, Professor of Biological Physics at the University of Edinburgh's School of Physics and Astronomy, said; "We would expect that the higher the level of toxins, the worse the disease. However, in this study we found that the lower the level of the protein, the more of these damaging short fibres we see. Understanding how these protein chains form offers us insight not only into how diseases progress, but how we can produce controlled biomaterials for tissue engineering."

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Variable Appearance of Neurodegenerative Diseases may be Explained by Shape-Shifting Disease Proteins

Researchers in the Perelman School of Medicine at the University of Pennsylvania have shown one disease protein can morph into different strains and promote misfolding of other disease proteins commonly found in Alzheimer's, Parkinson's and other related neurodegenerative diseases.

Virginia M.Y. Lee, PhD, MBA, professor of Pathology and Laboratory Medicine and director of the Center for Neurodegenerative Disease Research, with co-director, John Q. Trojanowski MD, PhD, postdoctoral fellow Jing L. Guo, PhD, and colleagues, discovered that alpha-synuclein, a protein that forms sticky clumps in the neurons of Parkinson's disease patients, can exist in at least two different structural shapes, or "strains," when it clumps into fibrils, despite having precisely the same chemical composition.

These two strains differ in their ability to promote fibril formation of normal alpha-synuclein, as well as the protein tau, which forms neurofibrillary tangles in individuals with Alzheimer's disease.

Importantly, these alpha-synuclein strains are not static; they somehow evolve, such that fibrils that initially cannot promote tau tangles acquire that ability after multiple rounds of "seeded" fibril formation in test tubes.

The findings appear in the July 3rd issue of Cell.

Morphed Misfolding Proteins Found In Overlapping Neurodegenerative Diseases

Tau and alpha-synuclein protein clumps are hallmarks of separate diseases - Alzheimer's and Parkinson's, respectively. Yet these two proteins are often found entangled in diseased brains of patients who may manifest symptoms of both disorders.

One possible explanation for this convergence of Alzheimer's and Parkinson's disease pathology in the same patient is a global disruption in protein folding. But, Guo and Lee showed that one strain of alpha-synuclein fibrils which cannot promote tau fibrillization actually evolved into another strain that could efficiently cause tau to fibrillize in cultured neurons, although both strains are identical at the amino acid sequence level. Guo and Lee called the starting conformation "Strain A," and the evolved conformation, "Strain B."

To figure out how A and B differ, Guo showed that the two strains folded into different shapes, as indicated by their differential reactivity to antibodies and sensitivity to protein-degrading enzymes. The two strains also differed in their ability to promote tau fibrillization and pathology in mouse brains, mimicking the results from cultured cells. When analyzing post-mortem brains of Parkinson's patients, the team found at least two distinct forms of pathological alpha-synuclein.

Lee and her team speculate that in humans, alpha-synuclein aggregates may shift their shapes as they pass from cell to cell (much like a cube of silly putty being re-shaped to form a sphere), possibly developing the ability to entangle other proteins such as tau along the way. That process, in turn, could theoretically yield distinct types of alpha-synuclein pathologies that are observed in different brain regions of Parkinson's disease patients.

While further research is needed to confirm and extend these findings, they have potentially significant implications for patients afflicted with Parkinson's and other neurodegenerative diseases. For example, Lee explains, they could account for some of the heterogeneity observed in Parkinson's disease. Different strains of pathological alpha-synuclein may promote formation of distinct types of alpha-synuclein aggregates that may or may not induce tau pathology in different brain regions and in different patients. That, in turn, could explain why some Parkinson's patients, for example, experience only motor impairments while others ultimately develop cognitive impairments.

The findings also have potential therapeutic implications, Lee says. By recognizing that pathological alpha-synuclein can exist in different forms that are linked with different impairments, researchers can now selectively target one or the other, or both, for instance with strain-selective antibodies.

"What we've found opens up new areas for developing therapies, and particularly immunotherapies, for Parkinson's and other neurodegenerative diseases," Lee says.

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Risk of Cancer Posed by CT Scans Should be Weighed Against Benefits in Diagnosing Diseases

The study findings are reported in the British Medical Journal today and involved researchers at eight other centres in Australia, Oxford University, and the International Agency for Research on Cancer in Lyon, France.

Professor Mathews said: "CT scans were very useful in providing detailed three dimensional pictures to diagnose or exclude disease in internal organs and in most cases, the benefits of having a scan clearly outweigh the risk of a later cancer. Nevertheless, our new findings will remind doctors to order CT scans only when there is a definite medical reason, and to insist that CT scans use the lowest possible X-ray dose'. he said.

"As an individual patient, your risk of cancer from a CT scan is very low. Nevertheless, it is clear from our study that if we reduce the number of scans performed in a large population, and continue to reduce the doses from individual scans, there will be a small but corresponding reduction in the number of cancers in later years."

It is well known that large doses of radiation can damage DNA and increase the risk of a later cancer. However, the radiation doses from CT scans are very small, and there has been uncertainty about whether such small doses would cause cancer, and whether any small increase in risk could be measured reliably.

This study answered questions by linking de-identified Medicare records of CT exposures for the entire population of young Australians, aged 0-19 years between 1985 and 2005, to cancers diagnosed up to the end of 2007.

The risk of cancer increased with the number of CT scans, and the proportional increase in risk was greater for those exposed at younger ages. Nevertheless, as CT usage increased with age, the majority of cancers in this study followed exposures in the teenage years. Although this study did not directly assess the effects of CT exposures after the age of 19, the results suggest that cancer risk will increase following CT scans in adult life.

With improvements in CT technology, the average radiation dose per scan is expected to fall, although CT scan numbers have continued to increase in many countries.

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