BAG1 restores DJ-1 chaperone function and dimerisation

DJ-1 (PARK7) is the encoded protein from one of the four chromosomal loci associated with autosomal recessive, early onset parkinsonism. While evidence from genetic and biochemical studies in murine and human cell lines indicates a role for DJ-1 as an antioxidant forming a homodimer, the function of DJ-1 still remains controversial. In our study, we demonstrate a protein interaction by co-immunoprecipitation between DJ-1 and BAG1 (Bcl-2-associated athanogene-1), which was found to be a regulator of Hsp70/Hsc70 family molecular chaperones inducing foldase activity in neurons. Moreover, we show that DJ-1/BAG1 protein interaction leads to changes in distribution and localisation of DJ-1 within the cell, which can be presented by a detailed analysis of the subcellular fractionation of DJ-1 and its mutant in the presence or absence of BAG1. Regarding the functional relevance of this interaction, we performed FRET (fluorescence resonance energy transfer) experiments demonstrating a clear increase in DJ-1 dimerisation in presence of BAG1. In intact neuronal cells, this increased dimerisation resulted in restoration of DJ-1 chaperone function as was shown by a new biosensor for chaperone foldase activity. Taken together, we show for the first time in situ that modulation of the chaperone protein folding machinery leads to a functional restoration of a mutant protein specific for a neurodegenerative disease.