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Subject: ALTERED PROTEIN SHAPES MAY EXPLAIN DIFFERENCES IN SOME BRAIN
DISEASES

U.S. Department of Health and Human Services NATIONAL INSTITUTES OF HEALTH
NIH News National Institute of Neurological Disorders and Stroke
(NINDS)<http://www.ninds.nih.gov/>
National Institute on Aging (NIA)<http://www.nia.nih.gov/> Embargoed for
Release: Wednesday, July 3, 2013, Noon EDT
                                           
CONTACT: Barbara McMakin, 301-496-5751,
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ALTERED PROTEIN SHAPES MAY EXPLAIN DIFFERENCES IN SOME BRAIN DISEASES
NIH-funded study finds that various strains of alpha-synuclein have diverse
effects in neurons

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 -- originating from the
same protein -- may lead to different patterns of misfolding that result in
neurological disorders with unique sets of symptoms. 

"This study has important implications for Parkinson's 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's 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."

An example of such a protein is alpha-synuclein, which can accumulate in
brain cells, causing synucleinopathies, multiple system atrophy, Parkinson's
disease, Parkinson's 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's 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.  

In the new study, published in Cell, 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.

The 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 -- earlier and across more brain regions -- compared to mice that
received strain A.  

The researchers also examined the brains of five patients who had PDD, some
of whom also had Alzheimer's. 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's brains, supporting the existence
of disease-specific strains of the protein in human diseases. 

"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's disease, PDD, or DLB to see if there
are differences in the distribution of alpha-synuclein strains." 

Although 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. 

"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."

She 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."

This study was supported by grants from NINDS (NS53488) and the National
Institute on Aging (AG17586). Additional funding was provided by the Marian
S. Ware Alzheimer Program, Philadelphia, PA; the Dr. Arthur Peck Fund,
Philadelphia, PA; The Jeff and Anne Keefer Fund, Philadelphia, PA; and the
Parkinson Council, Bala Cynwyd, PA.

NINDS <http://www.ninds.nih.gov> is the nation's leading funder of research
on the brain and nervous system. The NINDS mission is to reduce the burden
of neurological disease - a burden borne by every age group, by every
segment of society, by people all over the world.

About the National Institutes of Health (NIH): NIH, the nation's medical
research agency, includes 27 Institutes and Centers and is a component of
the U.S. Department of Health and Human Services. NIH is the primary federal
agency conducting and supporting basic, clinical, and translational medical
research, and is investigating the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and its programs,
visit <www.nih.gov>.

NIH...Turning Discovery into Health -- Registered, U.S. Patent and Trademark
Office.
-----------
The news release contains an image of the effect of strain B on mouse cells
at <http://www.ninds.nih.gov/img/red_green_mouse_brain_cells.jpg>
CAPTION: 
Accumulations of alpha-synuclein (red) and tau (green) were found in mouse
brain cells that had been treated with strain B. Overlap of the two proteins
is shown in yellow. Courtesy of Dr. Virginia M.Y. Lee, University of
Pennsylvania School of Medicine.
 
REFERENCES:
Jing L. Guo et al. "Distinct a-Synuclein Strains Differentially Promote tau
Inclusions in Neurons." Cell, July 3, 2013. DOI: 10.1016/j.cell.2013.05.057

For more information about Parkinson's disease and dementia with Lewy
bodies, please visit:  
<http://www.ninds.nih.gov/disorders/parkinsons_disease/parkinsons_disease.ht
m>
<http://www.ninds.nih.gov/disorders/dementiawithlewybodies/dementiawithlewyb
odies.htm>

###

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