The protein oxidation repair enzyme methionine sulfoxide reductase a modulates Aβ aggregation and toxicity in vivo.

Abstract

AIMS:

To examine the role of the enzyme methionine sulfoxide reductase A-1 (MSRA-1) in amyloid-β peptide (Aβ)-peptide aggregation and toxicity in vivo, using a Caenorhabditis elegans model of the human amyloidogenic disease inclusion body myositis.

RESULTS:

MSRA-1 specifically reduces oxidized methionines in proteins. Therefore, a deletion of the msra-1 gene was introduced into transgenic C. elegans worms that express the Aβ-peptide in muscle cells to prevent the reduction of oxidized methionines in proteins. In a constitutive transgenic Aβ strain that lacks MSRA-1, the number of amyloid aggregates decreases while the number of oligomeric Aβ species increases. These results correlate with enhanced synaptic dysfunction and mislocalization of the nicotinic acetylcholine receptor ACR-16 at the neuromuscular junction (NMJ).

INNOVATION:

This approach aims at modulating the oxidation of Aβ in vivo indirectly by dismantling the methionine sulfoxide repair system. The evidence presented here shows that the absence of MSRA-1 influences Aβ aggregation and aggravates locomotor behavior and NMJ dysfunction. The results suggest that therapies which boost the activity of the Msr system could have a beneficial effect in managing amyloidogenic pathologies.

CONCLUSION:

The absence of MSRA-1 modulates Aβ-peptide aggregation and increments its deleterious effects in vivo.

• Authors: Alicia N Minniti, Macarena S Arrazola, Marcela Bravo-Zehnder, Francisca Ramos, Nibaldo C Inestrosa, Rebeca Aldunate
• Journal: Antioxidants & redox signaling (Antioxid Redox Signal) Vol. 22 Issue 1 Pg. 48-62 (Jan 01 2015) ISSN: 1557-7716 [Electronic] United States
• PMID: 24988428 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• Caenorhabditis elegans Proteins
• Receptors, Nicotinic
• acr-16 protein, C elegans
• Methionine
• Methionine Sulfoxide Reductases

Topics

• Amyloid beta-Peptides (metabolism)
• Animals
• Animals, Genetically Modified
• Blotting, Western
• Caenorhabditis elegans (metabolism)
• Caenorhabditis elegans Proteins (metabolism)
• Immunoprecipitation
• Locomotion (physiology)
• Methionine
• Methionine Sulfoxide Reductases (metabolism)
• Oxidation-Reduction
• Receptors, Nicotinic (metabolism)