Important steps in how Parkinson's disease (PD) spreads from cell
to cell and leads to nerve cell death.
Their line of research also informs the general concept that this
type of disease progression is a common pathway for such other
neurodegenerative diseases as Alzheimer's, Huntington's, progressive supranuclear
palsy, and possibly amyotrophic lateral sclerosis (ALS).
The Penn team found that injecting synthetic, misfolded and
fibrillar α-Synuclein (α-Syn) -- the PD disease protein -- into the brains of
normal, "wild-type" mice recapitulates the cascade of cellular demise
seen in human PD patients.
Parkinson's disease is characterized by abundant α-Syn clumps in
neurons and the massive loss of midbrain dopamine-producing neurons. However, a
cause-and-effect relationship between the formation of α-Syn clumps and
neurodegeneration has been unclear.
In short, the Penn researchers found that, in healthy mice, a
single injection of synthetic, misfolded α-Syn fibrils led to a cell-to-cell
transmission of pathologic α-Syn proteins and the formation of Parkinson's α-Syn
clumps known as Lewy bodies in interconnected regions of the brain. Their
findings appear in this week's issue ofScience. The team was led by
senior author Virginia M.-Y Lee, PhD, director of the Center for
Neurodegenerative Disease Research (CNDR) and professor of Pathology and
Laboratory Medicine, and first author Kelvin C. Luk, PhD, research assistant
professor in the CNDR.
The major significance of the paper is that it resolves the
long-standing controversy about the role of α-Syn Lewy bodies in the degeneration
of substantia nigra dopamine neurons, thereby sharpening the focus on Lewy
bodies as targets for discovery of disease modifying therapy for Parkinson
patients.
The α-Syn clumps caused progressive loss of dopamine neurons in
the connected substantia nigra region of the brain. This finding was
accompanied by reduced dopamine levels in the neurons of the striatum, which
cause the movement disorder in Parkinson's patients. The team saw α-Syn
pathology in the wild-type mice one month after injection. After three months
one sixth of dopamine-producing neurons were gone and after six months half of
dopamine-producing neurons were gone. In addition, the injected wild-type mice
did worse on motor skill tests of grip strength, balance, and co-ordination compared
to controls. The experiment was ended before cognitive defects were detected,
which is common in about 80 percent of Parkinson's patients during the course
of the illness.
The recapitulation of the neurodegenerative demise of neurons
establishes a mechanistic link between transmission of pathologic α-Syn and the
cardinal features of Parkinson's disease -- death of dopamine-producing neurons
and the formation of α-Syn clumps.
Pathological Templates Two years ago, the same Penn team found
that small amounts of misfolded α-Syn can be taken up by healthy neurons,
replicating within the nerve cells to cause neurodegeneration. The α-Syn
protein is normally found in brain synapses that connect nerve cells and enable
their communication.
In time, α-Syn forms the characteristic Lewy bodies in the neurons
of patients with PD and some other neurodegenerative disorders. They found that
abnormal clumps of α-Syn formed by small fibrils act as "seeds" that
induce normal α-Syn molecules to misfold and form aggregates. This scenario
then propagates from neuron to neuron over time in the brain. The pathological
α-Syn acts as a template to corrupt the normal α-Syn so it too becomes
pathological and thereby spreads the disease from an affected neuron to a
normal one, which then becomes diseased.
In earlier studies at other institutions, when fetal nerve cells
were transplanted into the brains of PD patients, some of the transplanted
cells developed Lewy bodies. This also suggested that the corrupted form of
α-Syn could somehow be transmitted from diseased neurons to healthy ones.
In a study published earlier in 2012 in the Journal of
Experimental Medicine, the Penn team showed that extracts of brain
tissue from a PD mouse model, as well as synthetically produced α-Syn fibrils,
injected into young, symptom-free transgenic mice that were engineered to
overexpress α-Syn led to spreading of α-Syn pathology. By three months after a
single injection, neurons containing abnormal α-Syn clumps were detected
throughout the mouse brains. The inoculated mice died between 100 to 125 days
post-inoculation, short of their typical two-year life span.
In contrast, the current Science study was conducted using
healthy, wild-type or non-transgenic mice. This means that since this PD was
induced in a healthy mouse, the researchers' approach is now a much more
compelling model for studying the most common form of PD -- sporadic PD, which
accounts for greater than 90 percent of patients with PD whose disease does not
run in families.
In addition, by using isolated, synthetic misfolded α-Syn, which
has same properties as natural α-Syn, and not brain tissue from PD patients or
PD mice, the researchers were able to establish that it was the misfiolded
α-Syn alone that unequivocally causes the pathology and progression of PD in
the healthy mice.
The team is now working on an antibody therapy in these mouse
models to stop propagation of rogue misfolded α-Syn. What's more, both the cell
culture and the mouse models will facilitate the identification of novel
targets for PD therapy.
Other Penn scientists who co-authored the study are Vicky Kehm,
Jenna Carroll, Bin Zhang Patrick O'Brien, and John Trojanowski. This work was
funded by the National Institutes of Neurological Disorders and Stroke Morris
K. Udall Parkinson's Disease Research Center of Excellence (NS053488), the JPB
and RJG Foundations, the Parkinson's Council and the Jeff and Anne Keefer Fund.
Source:
The above story is reprinted from materials provided by Perelman
School of Medicine at the University of Pennsylvania.
Note: Materials may be edited for content and length.
For further information, please contact the source cited above.
Journal References:
1. K. C. Luk, V. M. Kehm, B. Zhang, P. O'Brien, J.
Q. Trojanowski, V. M. Y. Lee. Intracerebral inoculation of pathological
-synuclein initiates a rapidly progressive neurodegenerative
-synucleinopathy in mice. Journal of Experimental Medicine,
2012; 209 (5): 975 DOI:10.1084/jem.20112457
2. K. C. Luk, V. Kehm, J. Carroll, B. Zhang, P.
O'Brien, J. Q. Trojanowski, V. M.- Y. Lee. Pathological
-Synuclein Transmission Initiates Parkinson-like Neurodegeneration in
Nontransgenic Mice. Science, 2012; 338 (6109): 949 DOI: 10.1126/science.1227157
Disclaimer: This article is not intended to provide
medical advice, diagnosis or treatment. Views expressed here do not necessarily
reflect those of Eagle Group or its staff.
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