Toxic Protein Complexes Promote Development of Multiple Neurodegenerative Disorders

Neuroscientists have identified a mechanism that explains why patients suffering from severe neurodegenerative diseases such as Alzheimer's disease often develop other syndromes such as Parkinson's disease and vice versa.

The mechanism is linked to the misfolding and pathologic aggregation of neuronal proteins, which has been proposed to play a critical role in the pathogenesis of neurodegenerative disorders. Progressive accumulation of amyloid beta protein (Abeta) oligomers has been identified as one of the central toxic events in Alzheimer's disease, while accumulation of alpha-synuclein (alpha-syn) results in the formation of oligomers and protofibrils in Parkinson's disease.

Investigators from the University of California, San Diego (San Diego, CA, USA) used immunoblots, molecular modeling, and in vitro studies performed with alpha-syn and Abeta in order to understand the molecular mechanisms involved in potential Abeta/alpha-syn interactions. They reported in the September 4, 2008, issue of the journal Public Library of Science (PLoS) ONE that Abeta and alpha-syn co-immunoprecipitated and formed complexes. Molecular modeling and simulations showed that Abeta bound alpha-syn monomers, homodimers, and trimers, forming hybrid ring-like pentamers. Interactions occurred between the N-terminus of Abeta and the N-terminus and C-terminus of alpha-syn. The stable pentamers acted as nanopores that altered neuronal activity and would likely contribute to the mechanisms of neurodegeneration in Alzheimer's and Parkinson's diseases.

"Clinically, we knew that having one neurological disease, such as Alzheimer's, put patients at risk for another neurological disease in combination with it, for example, Parkinson's disease or frontotemporal dementia. But as doctors and scientists, we did not understand why this occurred until now,” explained senior author Dr. Eliezer Masliah, professor of neurosciences and pathology at the University of California, San Diego. "This sort of modeling, to determine the structure of these complexes, was never before possible. With this novel technology, we have come to a new understanding of these combined neurological diseases, and have a model for developing new drugs to treat them.”

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