The Protein Oxidation Repair Enzyme Methionine Sulfoxide Reductase A Modulates Aβ Aggregation and ToxicityIn Vivo

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. Antioxid. Redox Signal. 22,[48][49][50][51][52][53][54][55][56][57][58][59][60][61][62]

Effect of methionine-35 oxidation on the aggregation of amyloid-β peptide

“…However, Met35 can play a role in AD pathogenesis due to putative interactions in the biological systems. It has been shown that in a Caenorhabditis elegans model of inclusion body myositis the knockout of MSRA-1 reduces the aggregation of Aβ into insoluble aggregates [33] , however in this case the aggregation is intracellular. Even small differences in the peptide aggregation properties may be crucial in triggering the molecular events leading to the disease, however the lower amyloidogenity and the unaffected ability to catalyze redox reactions when bound to copper ions suggest that Met35 oxidation is most likely not essential in AD.…”

Defective protein repair under methionine sulfoxide A deletion drives autophagy and ARE-dependent gene transcription

“…Accordingly, the expression of antioxidant proteins via the Nrf2-antioxidant response element (ARE)-signaling pathway is upregulated when MsrA is missing [15] , [16] , [17] . Moreover, low activity of MsrA has been associated with formation of protein aggregates in Parkinson's and Alzheimer's disease as well as inclusion body myositis [18] , [19] , [20] , [21] , but the implications of these protein aggregates on repair and cell death pathways in MsrA deletion models has remained unstudied. In models of neurodegenerative diseases and proteinopathies of the liver, misfolded or unrepaired defective proteins colocalize with p62, also called sequestosome 1 (SQSTM1), a ubiquitin-binding scaffold protein [22] , [23] .…”

Intracellular repair of oxidation-damaged α-synuclein fails to target C-terminal modification sites

“…In addition, different organelle-specific MSR isoforms are present 26 27 . Loss of MSR activity results in augmented brain pathologies associated with neurodegenerative disorders, such as Alzheimer's disease and PD 28 29 30 , and MSRs are thought to exert general protective effects against α-Syn aggregation and cellular oxidative stress-induced apoptosis 31 .…”