Presynaptic crosstalk of autophagy and proteasomal activity to maintain proteostasis

JANINE KIRSTEIN (Universität Bremen & Leibniz Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin)
BRITTA EICKHOLT (Charité-Universitätsmedizin, Berlin)

Ageing is marked by an accumulation of misfolded and damaged proteins that severely compromise the physiology of a cell and an organism. Accordingly, damaged proteins need to get eliminated to maintain cellular function throughout life. This is of particular importance in post-mitotic cells such as neurons. The two major proteolytic machines are macro-autophagy and the ubiquitin proteasome system (UPS). We are only beginning to understand how both proteolytic pathways are organized on a cellular level and at subcellular locations such as the presynapse, and how they may change throughout the lifetime of an organism. In a joint project between the Kirstein lab (Universität Bremen) and Eickholt lab (Charité-Universitätsmedizin, Berlin), the crosstalk and/or compensatory mechanisms between autophagy and UPS will be explored. We will study the capacities of both proteolytic pathways at the presynapse with the progression of ageing and investigate effector systems that mediate a crosstalk between autophagy and the UPS. We further aim to identify novel presynaptic autophagy substrates using a strategy involving an engineered chaperone system. For that, we will use the nematode Caenorhabditis elegans, mice and cultured neurons as model system and utilize protein engineering to trap and identify autophagy substrates. We will employ state of the art imaging techniques including, super resolution microscopy, photo-conversion, FLIM and optogenetic tools as well as protein engineering.

Overview of the regulatory inputs on the crosstalk between autophagy and UPS that will be analyzed in the joint project (left). Analyses will be conducted in mice, cultured neurons and C. elegans (right).

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Kreis P, Gallrein C, …, Kirstein J*, Eickholt BJ* (2019) ATM phosphorylation of the actin-binding protein drebrin controls oxidation stress-resistance in mammalian neurons and C. elegans. Nat Commun 10, 486.

Feleciano DR, …, Kirstein J (2019) Crosstalk Between Chaperone-Mediated Protein Disaggregation and Proteolytic Pathways in Aging and Disease. Front. Aging Neurosci. 11, 9

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