PHILADELPHIA - Research from the Perelman School of Medicine at the University of Pennsylvania has found that small amounts of misshapened brain proteins can be taken up by healthy neurons and replicated within them to cause neurodegeneration. The research, published in Neuron, shows a way that Parkinson’s disease (PD) can spread in the brain and provides a model for discovering therapeutics targeting PD neurodegeneration.
Alpha-synuclein (a-syn) is a brain protein that forms clumps called Lewy bodies, the hallmark of PD and other neurodegenerative disorders.
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 suggests that healthy cells take up abnormal extracellular a-syn, which “recruits” normal a-syn into clumps. However, it is not clear whether the Lewy bodies were formed by the spread of abnormal a-syn fibrils or if the neighboring diseased neurons exerted some other toxic influence that caused young grafted neurons to form Lewy bodies.
"We examined whether exposure of neurons to a-syn fibrils recruited normal a-syn in these neurons to form Lewy bodies,” explains senior author Virginia M.-Y Lee, PhD, director of the Center for Neurodegenerative Disease Research and professor of Pathology and Laboratory Medicine. “We performed our experiments using synthetic a-syn fibrils and normal neurons, similar to the physiological conditions seen in the majority of sporadic PD patients.”
They found that the a-syn fibrils acted as “seeds” that induced normal a-syn to aggregate into clumps. The fibrils were taken up by nerve cell extensions, spread to the cell body where PD-like Lewy bodies formed that impaired neuronal function and led to the death of this neuron. This suggests that abnormal a-syn can amplify and propagate PD-like Lewy bodies throughout the nervous system.
This research was funded by the National Institutes of Health for the Penn Udall Center, the Picower Foundation, the Jeff Keefer Foundation, the Parkinson Council, and the Stein-Bellet Family Foundation.
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