The anti-amyloidogenic chaperone DNAJB6 and its interaction with other chaperones

Sammanfattning: In order to maintain proteins’ functionality their native folding state must be preserved. Chaperones fold other proteins and DNAJ-chaperones may collaborate with Hsc70 chaperones to prevent aggregation of aggregation-prone peptides such as polyQ and Aβ42, which form fibrils in currently incurable diseases as Huntington’s and Alzheimer’s, respectively. Fibril formation of polyQ and Aβ42 is detected by ThT fluorescence measurements over time and halftime values (t​1/2 values) of fibril formation can be calculated and used to determine how chaperones can suppress fibril formation which is observed as increased t​1/2 value. Here we observed that there is an enhancement of the DNAJB6 suppression of fibril formation by Aβ42 in the trimeric chaperone system with DNAJB6, Hsc70, Hsp110 and ATP. The increased t​1/2 values observed with the trimeric chaperone system is dependent on ATP-hydrolysis since the effect was reversed (decreased t​1/2 values) in absence of Hsp110, the nucleotide-exchange factor. Moreover, the effects were different with ATP, ADP or a non-hydrolyzable ATP-analogue. A possible interpretation is that the observed enhancement here, for the first time with DNAJB6 in the trimeric chaperone system, is the result of a continuous capture of Aβ42 oligomers, which otherwise function as nuclei for fibril formation, and continuous release as Aβ42 oligomers under ATP-hydrolysis.