Affiliations: [a] Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada | [b] Department of Chemistry, McMaster University, Hamilton, ON, Canada
Correspondence:
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Corresponding author: Joaquin Ortega, Department of Biochemistry and Biomedical Sciences, Health Sciences Centre, Room 4H24, McMaster University, 1200 Main Street West, Hamilton, ON, L8N3Z5, Canada. Tel.: +1 905 525 9140 Ext 22703; Fax: +1 905 522 9033; E-mail: [email protected].
Note: [] Communicated by Jesus Avila
Abstract: Human HtrA2 is part of the HtrA family of ATP-independent serine proteases that are conserved in both prokaryotes and eukaryotes and localizes to the intermembrane space of the mitochondria. Several recent reports have suggested that HtrA2 is important for maintaining proper mitochondrial homeostasis and may play a role in Alzheimer's disease (AD), which is characterized by the presence of aggregates of the amyloid-β peptide 1–42 (Aβ1-42). In this study, we analyzed the ability of HtrA2 to delay the aggregation of the model substrate citrate synthase (CS) and of the toxic Aβ1-42 peptide. We found that HtrA2 had a moderate ability to delay the aggregation of CS in vitro, and this activity was significantly enhanced when the PDZ domain was removed suggesting an inhibitory role for this domain on the activity. Additionally, using electron microscopy and nuclear magnetic resonance analyses, we observed that HtrA2 significantly delayed the aggregation of the Aβ1-42 peptide. Interestingly, the protease activity of HtrA2 and its PDZ domain were not essential for the delay of Aβ1-42 peptide aggregation. These results indicate that besides its protease activity, HtrA2 also performs a chaperone function and suggest a role for HtrA2 in the metabolism of intracellular Aβ and in AD.
Keywords: Alzheimer's disease, amyloid-β42, amyloid-β protein precursor, electron microscopy, HtrA2, nuclear magnetic resonance
