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Human Protein May Lead To New Therapeutic Strategies
June 29, 2017

A naturally occurring human enzyme –called cyclophilin 40 or CyP40– can unravel protein aggregates that contribute to both Alzheimer’s disease and Parkinson’s disease, reports a study led by researchers at the University of South Florida (USF) in Tampa and published recently in the open access journal PLOS Biology. According to information provided by USF, the finding may point toward a new therapeutic strategy for these diseases.

According to Laura Blair, Ph.D., an assistant professor in the Department of Molecular Medicine at the USF Health Byrd Alzheimer’s Institute, this is the first time that CyP40 has been shown to disaggregate, or dissolve, a toxic, soluble form of amyloid responsible for a neurodegenerative disease. Dr. Blair and fellow USF researchers, including Jeremy Baker, a doctoral candidate in the Department of Molecular Medicine and a lead author on the PLOS Biology paper, worked with colleagues from several institutions in Germany.

The study found that CyP40 could reduce the amount of aggregated tau, converting it into a more soluble and less toxic form. In a mouse model of an Alzheimer’s-like disease, experimental expression of CyP40 preserved brain neurons and rescued cognitive deficits. The same enzyme also disaggregated alpha-synuclein, an aggregate associated with Parkinson’s disease.

In most neurodegenerative diseases, misfolded proteins accumulate abnormally to form an insoluble clump called amyloid. Many amyloid-forming proteins, including tau in Alzheimer’s disease and ?-synuclein in Parkinson’s disease, contain the amino acid proline, which has a unique structure inducing a bend in the amino acid chain. Those bends contribute to stacking of adjacent regions of the protein promoting clumping. CyP40 may dissolve these insoluble clumps by interacting with prolines within the amyloid structure.

Exactly how CyP40 reduces aggregation is not yet clear, and the authors provide two possibilities. The enzyme may bind to aggregated protein and, by reversing the proline bend, help unstack and separate the amino acid chain. Support for this model comes from the observation that the enzyme was less effective at reducing aggregates when its action was inhibited. Alternatively, the enzyme may bind to the protein before it forms aggregates, sequestering it and thus preventing the potentially harmful clumping.

“The finding that Cyp40 can untangle clumps of tau and alpha-synuclein suggests that it, or one of the more than 40 other human proteins with similar activity, may have a role to play in treating neurodegenerative disease,” Dr. Blair said.

The study was supported by grants from the National Institutes of Health, the Alzheimer’s Association and the Veterans Health Administration.

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