University of South Florida

A human enzyme can reduce neurotoxic amyloids in mouse model of dementia

The USF-led study suggests CyP40 or similar proteins may be potential therapeutics for Alzheimer’s and Parkinson’s diseases

TAMPA, Fla. (June 27, 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 in Tampa and published today in the open access journal PLOS Biology. The finding may point toward a new therapeutic strategy for these diseases.

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, according to Laura Blair, PhD, an assistant professor in the Department of Molecular Medicine at the USF Health Byrd Alzheimer’s Institute.  Blair and fellow USF researchers worked with colleagues from several institutions in Germany.

USF neuroscientist Laura Blair, PhD, principal investigator for the study, in her laboratory at the USF Health Byrd Alzheimer’s Institute.

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 α-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.

Dr. Blair with Jeremy Baker, a doctoral candidate in the Department of Molecular Medicine and a lead author on the PLOS Biology paper. Pictured on the monitor are tau oligomers.

Understanding more specifically how the enzyme works may help point toward a therapeutic strategy centered on proline’s role in amyloid formation.

“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,” Blair said.

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

Human cyclophilin 40 unravels neurotoxic amyloids; Jeremy D. Baker, Lindsey B. Shelton, Dali Zheng, Filippo Favretto, Bryce A. Nordhues, April Darling, Leia E. Sullivan, Zheying Sun1, Parth K. Solanki, Mackenzie D. Martin, Amirthaa Suntharalingam, Jonathan J. Sabbagh, Stefan Becker, Eckhard Mandelkow, Vladimir N. Uversky, Markus Zweckstetter, Chad A. Dickey, John Koren III, and Laura J. Blair; PLOS Biology; June 27, 2017;

– Photos by Eric Younghans, USF Health Communications and Marketing

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