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