PHILADELPHIA — 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 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 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 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.

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