Antioxid Redox Signal. 2015 Jan 1;22(1):48-62.

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

Alicia N. Minniti1, Macarena S. Arrazola 1,2, Marcela Bravo-Zehnder2, Francisca Ramos3, Nibaldo C. Inestrosa 1,2 and Rebeca Aldunate 1,2,3

1 Facultad de Ciencias Biologicas, Pontificia Universidad Catolica de Chile. 2 Center for Aging and Regeneration (CARE).3 Escuela de Biotecnologia, Facultad de Ciencias, Universidad Santo Tomas. Santiago, Chile

rebecaaldunatem@gmail.com

 

ABSTRACT

Aims: To examine the role of the enzyme methionine sulfoxide reductase A-1 (MSRA-1) in amyloid-b peptide (Ab)-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 Ab-peptide in muscle cells to prevent the reduction of oxidized methionines in proteins. In a constitutive transgenic Ab strain that lacks MSRA-1, the number of amyloid aggregates decreases while the number of oligomeric Ab 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 Ab in vivo indirectly by dismantling the methionine sulfoxide repair system. The evidence presented here shows that the absence of MSRA-1 influences Ab 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 Ab-peptide aggregation and increments its deleterious effects in vivo.

PMID: 24988428

 

SUPPLEMENTARY

Sporadic inclusion body myositis (IBM) is the most common muscle disease in the elderly. It affects the skeletal muscles and its progression leads to severe muscle weakness. Currently, there is no effective treatment for this disease. One of the most notable characteristics of IBM is the presence of intracellular amyloid-β peptide aggregates in skeletal muscle fibers, which has a crucial role in the development of IBM, similar to what occurs in Alzheimer’s disease (AD).

The study by Minniti et al. focuses on investigating the role of Aβ-peptide Met35 redox state on its aggregation and toxicity in vivo, using a C. elegans model of the human amyloidogenic disease IBM. The Ab peptide has only one methionine at position 35. There is controversial in vitro evidence showing that the oxidation in this particular amino acid influences the peptide’s aggregation and toxicity.

In order to be able to modulate Ab Met35 oxidation state in vivo the authors used an original strategy. They introduced a deletion of the gene that encodes the methionine sulfoxide reductase A enzyme (MSRA-1) into a transgenic C. elegans strain that expresses the human Ab peptide. The absence of this enzyme ensures the permanent oxidation of Met35 in the Ab peptide. The methionine sulfoxide reductase system, which exclusively repairs oxidized methionines, is highly conserved from bacteria to mammals. Therefore, the results from this study could be relevant to humans.

Minniti et al. found that the absence of MSRA-1 is critical during early stages of IBM, being a key factor in its aggregation and toxicity in vivo. This study highlights the relevance of the methionine sulfoxide reductase system in IBM pathology. The authors show that, in the transgenic Ab strain that lacks MSRA-1, the number of amyloid aggregates decreases while the number of toxic oligomeric Ab species increases. In this model, the temporal progression of the disease, associated with the loss of synaptic function, is accelerated in the absence of MSRA-1. Synaptic dysfunction associates with mislocalization of the nicotinic acetylcholine receptor ACR-16 (a7 nAChR homolog) at the neuromuscular junction. The locomotor impairments are aggravated and correlate with and structural and functional alterations of the neuromuscular junction.

Therapies that improve the activity of this antioxidant system could be beneficial in managing amyloidogenic diseases such a s IBM and AD.

 

 

figure 1 RA

 

 

 

 

 

 

Multiselect Ultimate Query Plugin by InoPlugs Web Design Vienna | Webdesign Wien and Juwelier SchönmannMultiselect Ultimate Query Plugin by InoPlugs Web Design Vienna | Webdesign Wien and Juwelier Schönmann