Unfolding the role of Ire1 and DNAJB1 in Parkinson’s disease

Abstract: Parkinson’s disease (PD) is a movement disorder of the brain which is hallmarked by the presence of large protein-rich cytoplasmic aggregates, called Lewy bodies (LBs), in the neurons. The protein α-synuclein (α-syn) is abundant in these aggregates, and can itself form aggregates. Several mutations linked to α-syn are also linked to an increased risk of contracting PD. In healthy neurons, the chaperone heat shock protein 70 (Hsp70) is able to refold misfolded proteins such as aggregated α-syn, with the help of its co-chaperones, the DNAJ proteins. In addition, toxic protein aggregation is normally stopped by the unfolded protein response (UPR) in the endoplasmic reticulum, including the protein Ire1 which indirectly activates genes involved in protein folding. Here, it is shown that knocking out the DNAJ protein DNAJB1 in HEK293 cells overexpressing α-syn, by use of CRISPR/Cas9 technology, leads to a significant increase of α-syn aggregates. In addition, reintroducing the DNAJB1 gene into these knockout cells decreases the aggregate percentage to a level comparable with control cells. Furthermore, introducing a H32Q mutant version of DNAJB1, which cannot interact with HSP70, into the knockout cells, does not decrease the level of α-syn aggregation. This suggests that the DNAJB1 protein may have an important function in suppressing the formation of the toxic α-syn aggregates in cells and could be involved in a potential new PD therapeutic. Furthermore, the effect of conditionally knocking out the UPR protein Ire1 in the dopaminergic neurons of a Parkinsonian mouse model expressing human α-syn-GFP has been investigated. After 6 months, the lack of the protein does not seem to result in a behavioral difference in the mice compared to control, and thereby does not share the therapeutic potential of DNAJB1.