DynProtect - Mechanisms of dynein-dependent transport and degradation of protein aggregates.

Accumulation of protein aggregates is a major threat to eukaryotic cells, and a hallmark of age-associated neurodegeneration, including Alzheimer's and Parkinson's disease. Basal mechanisms to dispose of aggregates largely rest on the pathways of proteasome-mediated degradation and selective autophagy. In contrast, cells react to extreme proteotoxic stress by actively transporting aggregates to the microtubule organising centre, where they coalesce into a specialised organelle, named the aggresome. The process depends on the minus-end directed motor dynein. With this fellowship, I will uncover the network of factors required to recruit dynein to aggregates and target them to the aggresome, and address whether the motor also plays a role in the basal clearance of aggregation.
Dynein transport is in the vast majority of cases mediated by specialised dynein activating adaptors. I will use mass spectrometry and computational methods to identify which activating adaptor mediates dynein recruitment to aggregates, and validate the interaction using biochemistry and cell biology. use live-cell imaging in neurons to identify which proteins are recruited to aggregates during transport and confirm their function with depletions. I will investigate whether transport pathways are still active under basal conditions. I will use a combination of AlphaFold and Cryo-EM to provide a comprehensive molecular understanding of the connections that link aggregates to cellular motors. The outputs of this fellowship will be of great interest to communities researching proteostasis, neurodegeneration and intracellular transport.