Regulation of aggrephagy by co-chaperones and assisting proteins

 

The co-chaperone BAG3 is involved in the autophagic clearance of aggregation-prone proteins (aggrephagy), such as the Alzheimer’s-associated protein tau. Aggrephagy dysfunctions play a deleterious role in the development of neurodegenerative diseases. This collaborative project aims to unveil the molecular and functional principles that regulate BAG3- and HDAC6-mediated aggrephagy in neurodegeneration. 

   The Kaulich Group will characterize ATG/Ub3 ligase-dependencies in BAG3-mediated aggrephagy by CRISPR genomics. More specifically, this part of the project will identify ubiquitin-system dependencies of BAG3-mediated autophagy and aggrephagy, characterize direct and redundancy-mediated ATG8 effects on BAG3-mediated aggrephagy, and map the BAG3-dependent functional autophagy and aggrephagy-landscape.

   The Behl group will profile the aggresomal content under different paradigms such as BAG3 or HDAC6 deficiency to functionally characterize the target proteins. To characterize the precise BAG3 dependency of target proteins such as mutant tau or SOD in vitro as well as in vivo, this project part will profile autophagosomes from different neuronal cell models and from murine brain tissues for different disease-associated BAG3 variants. Together with the Kaulich group, we will dissect the mechanistic basis of BAG3-mediated aggrephagy in detail at the genomic and proteomic level.

  The Heilemann group will develop fluorescence imaging methods for long acquisition times with high temporal resolution to follow the structural dynamics in BAG3-mediated aggrephagy in living cells across time scales. Two strategies will be followed: (i) the employment of renewable fluorophore labels that facilitate bleaching-independent fluorescence microscopy, and (ii) the integration of neural networks for content restoration in low-intensity microscopy.

  Together, this project will clarify the role of aggrephagy in protein aggregation diseases and pin down targetable, decisive control factors of this selective autophagy process.

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