It only takes one bad apple to spoil the bunch, and the same may be true of certain proteins in the brain. Studies have suggested that just one rogue protein (in this case, a protein that is misfolded or shaped the wrong way) can act as a seed, leading to the misfolding of nearby proteins. According to an NIH-funded study, various forms of these seeds \u2014 originating from the same protein \u2014 may lead to different patterns of misfolding that result in neurological disorders with unique sets of symptoms.
\n‘This study has important implications for Parkinson\u2019s disease and other neurodegenerative disorders,’ said National Institute of Neurological Disorders and Stroke (NINDS) Director Story Landis, Ph.D. ‘We know that among patients with Parkinson\u2019s disease, there are variations in the way that the disorder affects the brains. This exciting new research provides a potential explanation for why those differences occur.’
\nAn example of such a protein is alpha-synuclein, which can accumulate in brain cells, causing synucleinopathies, multiple system atrophy, Parkinson\u2019s disease, Parkinson\u2019s disease with dementia (PDD), and dementia with Lewy bodies (DLB). In addition, misfolded proteins other than alpha-synuclein sometimes aggregate, or accumulate, in the same brains. For example, tau protein collects into aggregates called tangles, which are the hallmark of Alzheimer\u2019s disease and are often found in PDD and DLB brains. Findings from this study raise the possibility that different structural shapes, or strains, of alpha-synuclein may contribute to the co-occurrence of synuclein and tau accumulations in PDD or DLB.
\nIn the new study Jing L. Guo, Ph.D., and her colleagues from the University of Pennsylvania Perelman School of Medicine, Philadelphia, wanted to see if different preparations of synthetic alpha-synuclein fibrils would behave differently in neurons that were in a petri dish as well as in mouse brains. They discovered two strains of alpha-synuclein with distinct seeding activity in cultured neurons: while one strain (strain A) resulted in accumulation of alpha-synuclein alone, the other strain (strain B) resulted in accumulations of both alpha-synuclein and tau.
\nThe researchers also injected strain A or strain B into the brains of mice engineered to make large amounts of human tau, and then monitored the formation of alpha-synuclein and tau aggregates at various time points. Mice that received injections of synuclein strain B showed more accumulation of tau \u2014 earlier and across more brain regions \u2014 compared to mice that received strain A.
\nThe researchers also examined the brains of five patients who had PDD, some of whom also had Alzheimer\u2019s. In this small sample, there was evidence of two different structural forms of alpha-synuclein, one in PDD brains and a distinctly different one in PDD\/Alzheimer\u2019s brains, supporting the existence of disease-specific strains of the protein in human diseases.
\n‘We are just starting to do work with human tissues,’ said Virginia M.Y. Lee, Ph.D., senior author of the study. ‘We are planning to look at the brains of patients who had Parkinson\u2019s disease, PDD, or DLB to see if there are differences in the distribution of alpha-synuclein strains.’
\nAlthough the two strains used in this study were created in test tubes, the authors noted that in human brains, where the environment is much more complicated, the chances of forming additional disease-related alpha-synuclein strains may be greater.
\n‘These different strains not only can convert normal alpha-synuclein into pathological alpha-synuclein within one cell, they also can morph into new strains as they pass from cell to cell, acquiring the ability to serve as a template to damage both normal alpha-synuclein and other proteins,’ said Dr. Lee. ‘So certain strains, but not all strains, can act as templates to influence the development of other pathologies, such as tau tangles.’
\nShe commented, ‘We are just beginning to understand some of these strains and there may be many others. We hope to find a way to identify strains that are relevant to human disease.’\nNINDS<\/link>\n","protected":false},"excerpt":{"rendered":"
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