Tau and alpha-Synuclein Proteins Encourage Each Other To Produce Brain Lesions

(Philadelphia, PA) - The amyloid lesions that cause Alzheimer's and Parkinson's disease are made of clumps of tangled proteins, but these clumps are composed of different protein subunits. Researchers at the University of Pennsylvania School of Medicine have discovered, however, that the tau proteins found in Alzheimer's disease and the alpha (a)-synuclein proteins found in Parkinson's disease can facilitate each other to form amyloid lesions in the laboratory.

Their findings, presented in this week's issue of Science, provide insights into the mechanisms underlying both diseases and suggest that therapeutics developed for one disease might be efficacious for both.

"We are trying to understand the basic pathological overlap between the different amyloid lesions that cause Alzheimer's and Parkinson's, " said Virginia M. -Y. Lee, PhD, professor in Penn's Department of Pathology and Laboratory Medicine and Director of Penn's Center for Neurodegenerative Disease Research (CNDR). "This fundamental relationship may explain why patients with one disease are more likely to exhibit signs of the other disease."

The researchers showed that the a-synuclein proteins that form Lewy bodies in Parkinson's disease can induce tau proteins to form the sort of fiber aggregates found in Alzheimer's disease. Moreover, interactions between the tau and the a-synuclein proteins can dramatically induce the formation of fibrous clumps of both proteins.

"This newly uncovered interaction between these two proteins suggests that therapeutic agents created to directly or indirectly inhibit the formation of one form of amyloid lesion might be effective for treating other forms of amyloid lesions," said Benoit Gaisson, PhD, lead author of the paper and researcher at the CNDR. "That is, a drug meant to keep Lewy bodies from forming to prevent Parkinson's disease might also help prevent tau tangles from forming in Alzheimer's disease."

The two proteins, tau and a-synuclein are naturally abundant in the brain, but have distinct functions. Tau has a binding role in the structures of neurons, while a-synuclein is thought to be involved in regulating communications in the synapses between neurons.

The researchers knew that the smaller of the two proteins, a-synuclein, could bind to itself in homogenous clumps. The tau protein, meanwhile, is larger and it requires co-factors to aid overcoming a folding threshold. While the Penn researchers initially demonstrated that a-synuclein could aid tau into forming fibers in a test tube, the researchers also wanted to know if this also occurred in vivo. Using mouse models, they were able to demonstrate that a-synuclein polymerization alone is sufficient to induce the assembly of tau clumps in cells of the brain. Moreover, they were able to demonstrate that the same phenomenon occurs in a similar group of individuals with a known genetic abnormality in the a-synuclein gene.

"After this initial step, we see a cycle begin to emerge," said Gaisson. "Tau and a-synuclein work together to promote and propagate each other's formation of fibrous clumps and, hence, the amyloid lesions that cause disease."

Other scientists involved in the research paper described here include Mark S. Forman, Makoto Huguchi, Charles L. Graves, Paul T. Kotzbauer, and John Q. Trojanowski from Penn; and Lawrence I. Golbe from the University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School.

Funding for this research was supported by the National Institutes on Aging and by a Pioneer Award from the Alzheimer's Association.

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Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $6.7 billion enterprise.

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