Venue : CARF
On zoom: https://u-bordeaux-fr.zoom.us/j/83810704899
Ænora Letourneur
Team : SynTeam
IMN
Title
The chaperone DNAJB6 as a regulator of alpha-synuclein aggregation in neuronal models of induced synucleinopathy
Abstract
The protein α-synuclein self-assembles into amyloid fibrils, found in the neuronal or glial inclusion observed in synucleinopathies. In vitro studies have characterized the aggregation mechanisms of the protein, but the processes that the cell can use to modulate this aggregation are still under investigation. We chose to work in models of induced synucleinopathy, both primary cultures and in adult mice brains.
We first look at a panel of molecular chaperones, which have been shown to be involved in this regulation, before focusing of DNAJB6. Indeed, we observed, with this protein, a specific relocalization of DNAJB6, condensed as punctae, to the neo-formed aggregates. This observation, combined with the studies showing DNAJB6 to have an affinity for amyloid structures, made us hypothesize that DNAJB6 had a functional role in the regulation of the induced synucleinopathy.
Indeed, functional studies then allowed us to observe an inhibition of the aggregation of α-syn when DNAJB6 is overexpressed, both in primary cultures and in mice brains. We deduced that this effect was due to a selective interaction of DNAJB6 with the fibrillar α-syn, and not the monomeric one. Furthermore, we were able to show that this inhibition of the aggregation was due to the activity of DNAJB6 alone and not, as we thought in the beginning, due to its involvement in a system also containing Hsp110 and Hsc70, for which DNAJB6 is a co-chaperone. Indeed, the mutated H31Q DNAJB6, which cannot interact with Hsc70, showed the same inhibitory effect as the wild-type DNAJB6. We confirmed this point by reconstituting in vitro the system and seeing that, in contrast with DNAJB1, DNAJB6 does not induce a disaggregase activity of the system on the α-syn fibrils.
Key words
alpha-synuclein ; synucleinopathy ; molecular chaperones ; DNAJB6 ; neurons