HSP110 dependent HSP70 disaggregation machinery mediates prion-like propagation of amyloidogenic proteins in metazoa [article]

Jessica Tittelmeier, Carl Alexander Sandhof, Heidrun Maja Ries, Silke Druffel-Augustin, Axel Mogk, Bernd Bukau, Carmen Nussbaum-Krammer
2019 bioRxiv   pre-print
The gradual accumulation and prion-like propagation of α-synuclein and other amyloidogenic proteins is associated with devastating neurodegenerative diseases. The metazoan disaggregation machinery, a specific combination of HSP70 and its co-chaperones, is able to disassemble α-synuclein fibrils in vitro, but the physiological consequence in vivo is unknown. To explore this, we used Caenorhabditis elegans models that exhibit pathological features of α-synuclein, such as misfolding, intercellular
more » ... spreading and toxicity. We inhibited the HSP70 disaggregase by depleting the crucial component HSP-110 and monitored the effect on α-synuclein related phenotypes. The knockdown (KD) of HSP-110 not only impaired HSP70 disaggregation activity and prevented the resolubilization of amorphous heat shock induced firefly luciferase aggregates, but also compromised the cellular folding capacity. In stark contrast, HSP-110 depletion reduced α-synuclein foci formation, cell-to-cell transmission and toxicity. Similar effects were observed for a polyQ model substrate, confirming that inhibition of HSP70 disaggregation function mitigates amyloid toxicity. These data demonstrate that the metazoan HSP70 disaggregation complex plays a critical role in the prion-like propagation of amyloid-type conformers. Therefore, the HSP70 disaggregation activity is a double-edged sword as it is essential for the maintenance of cellular proteostasis while being involved in the generation of toxic amyloid-type protein species.
doi:10.1101/795435 fatcat:uxdnd4f5hfemlmvunxmazrn6je