Project Details
Projekt
Regulation of neuron-specific UPS and autophagy with aging
Subject Area
Molecular and Cellular Neurology and Neuropathology
Term
since 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 447288260
Neuronal network function critically depends on precise protein regulation, especially at synapses, where local protein degradation maintains synaptic plasticity. This degradation is primarily carried out by the ubiquitin-proteasome system (UPS) and autophagy. Although both pathways are essential, their regulation, particularly during aging when protein misfolding and aggregation become more common, remains poorly understood. Emerging evidence suggests significant interaction between UPS and autophagy, challenging the traditional view of them as separate mechanisms. This joint project betwenn the Eickholt and Kirstein labs aims to uncover how proteolytic pathways are regulated to maintain presynaptic proteostasis and protect synapses from age-related decline. Using a combination of C. elegans, mice, and cultured neurons, the study will explore these mechanisms from the molecular to the organismal level. A key focus is on the signaling kinase ATM that we identified in the first funding period as regulator of autophagy at the synapse, to determine how ATM spatially and temporally regulates protein degradation at synapses. We will study how ATM controls ATG9-dependent autophagosome formation, affects vesicle dynamics, and how these processes change with age. Advanced techniques like proximity labeling will be used to identify ATM’s location in neurons and its downstream molecular targets involved in the regulation of autophagy. The second focus will be on the proteolytic differences between brain areas and specific neurons to test the hypothesis that neuronal vulnerability is determined by their proteolytic capacity to eliminate damaged proteins that accumulate with aging. We will study the proteolytic activity and their regulation and will analyze the neuron-specific proteome of vulnerable vs resilient neurons to identify regulatory components and proteolytic substrates. Overall, this project seeks to provide critical insight into how proteostasis supports synaptic function and could lead to new therapeutic strategies for neurodegenerative diseases linked to impaired protein degradation.
DFG Programme
Research Units
