Parkinson ‘s disease protein causes disease spread and neuron death in healthy animals

ScienceDaily (Nov. 15, 2012) Understanding how any disease progresses is one of the first and most important steps towards finding treatments to stop it. This has been the case for such brain-degenerating conditions as Alzheimer's disease. Now, after several years of incremental study, researchers at the Perelman School of Medicine, University of Pennsylvania have been able to piece together 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 -Synuclein (-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 -Syn clumps in neurons and the massive loss of midbrain dopamine-producing neurons. However, a cause-and-effect relationship between the formation of -Syn clumps and neurodegeneration has been unclear.

In short, the Penn researchers found that, in healthy mice, a single injection of synthetic, misfolded -Syn fibrils led to a cell-to-cell transmission of pathologic -Syn proteins and the formation of Parkinson's -Syn clumps known as Lewy bodies in interconnected regions of the brain. Their findings appear in this week's issue of Science. 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 -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 -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 -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 -Syn and the cardinal features of Parkinson's disease -- death of dopamine-producing neurons and the formation of -Syn clumps.

Pathological Templates Two years ago, the same Penn team found that small amounts of misfolded -Syn can be taken up by healthy neurons, replicating within the nerve cells to cause neurodegeneration. The -Syn protein is normally found in brain synapses that connect nerve cells and enable their communication.

In time, -Syn forms the characteristic Lewy bodies in the neurons of patients with PD and some other neurodegenerative disorders. They found that abnormal clumps of -Syn formed by small fibrils act as "seeds" that induce normal -Syn molecules to misfold and form aggregates. This scenario then propagates from neuron to neuron over time in the brain. The pathological -Syn acts as a template to corrupt the normal -Syn so it too becomes pathological and thereby spreads the disease from an affected neuron to a normal one, which then becomes diseased.

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Parkinson 's disease protein causes disease spread and neuron death in healthy animals