New! Sign up for our free email newsletter.
Science News
from research organizations

Human enzyme can reduce neurotoxic amyloids in a mouse model of dementia

Date:
June 27, 2017
Source:
PLOS
Summary:
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, according to a study. The finding may point toward a new therapeutic strategy for these diseases.
Share:
FULL STORY

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, according to a study publishing June 27 in the open access journal PLOS Biology by Jeremy Baker, Laura Blair, and Chad Dickey of the University of South Florida in Tampa, and colleagues. The finding may point toward a new therapeutic strategy for these diseases.

In most neurodegenerative diseases, misfolded proteins aggregate to form an insoluble clump called amyloid. Many amyloid-forming proteins, including tau in Alzheimer's disease and alpha-synuclein in Parkinson's disease, contain the amino acid proline, whose unique structure induces a bend in the amino acid chain. Those bends contribute to stacking of adjacent regions of the protein, thus promoting amyloid formation. During normal protein folding, CyP40 latches on to prolines, orienting them into their characteristic chain-bending conformation, but like most enzymes, it can also operate in reverse, helping to unbend the chain.

The researchers found that CyP40 could reduce the amount of aggregated tau, converting it into a more soluble 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. This is the first time that CyP40 has been shown to disaggregate an amyloid responsible for a neurodegenerative disease.

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 it from clumping.

Understanding more about the exact mechanism of the enzyme 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.


Story Source:

Materials provided by PLOS. Note: Content may be edited for style and length.


Journal Reference:

  1. Jeremy D. Baker, Lindsey B. Shelton, Dali Zheng, Filippo Favretto, Bryce A. Nordhues, April Darling, Leia E. Sullivan, Zheying Sun, 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, Laura J. Blair. Human cyclophilin 40 unravels neurotoxic amyloids. PLOS Biology, 2017; 15 (6): e2001336 DOI: 10.1371/journal.pbio.2001336

Cite This Page:

PLOS. "Human enzyme can reduce neurotoxic amyloids in a mouse model of dementia." ScienceDaily. ScienceDaily, 27 June 2017. <www.sciencedaily.com/releases/2017/06/170627142846.htm>.
PLOS. (2017, June 27). Human enzyme can reduce neurotoxic amyloids in a mouse model of dementia. ScienceDaily. Retrieved March 28, 2024 from www.sciencedaily.com/releases/2017/06/170627142846.htm
PLOS. "Human enzyme can reduce neurotoxic amyloids in a mouse model of dementia." ScienceDaily. www.sciencedaily.com/releases/2017/06/170627142846.htm (accessed March 28, 2024).

Explore More

from ScienceDaily

RELATED STORIES