Project Details
Projekt
The role of neuronal β₂-adrenergic receptors in the regulation of non-canonical autophagy in vivo
Applicant
Anna Karpova, Ph.D.
Subject Area
Molecular Biology and Physiology of Neurons and Glial Cells
Term
since 2026
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 447288260
Emerging evidence indicates that neuronal autophagy extends beyond its canonical degradative role, functioning as an integrative platform for both degradation and intracellular signaling. A prominent example of this dual function is the signaling amphisome - a hybrid organelle formed by the fusion of autophagosomes with late endosomes. During retrograde axonal transport in neurons, amphisomes support local signal transduction at en passant presynaptic release sites and modulate neurotransmission. Upon arrival at the soma, amphisomes typically fuse with lysosomes to form autolysosomes. Alternatively, under conditions in which the endo-lysosomal system is compromised, neurons may engage a non-canonical secretory form of autophagy. Neurons of the locus coeruleus are the most metabolically burdened and degeneration-prone cells in the central nervous system. Accordingly, to maintain proteostasis in relation to their activity is extremely challenging. Our overarching hypothesis is that the extreme complexity of LC axonal arbors, combined with volume transmission and elevated metabolic demands, has led to ways of alternative, non-canonical autophagy pathways involving autocrine activation of β-adrenergic receptors. In this project, we aim to elucidate how β₂-AR-signaling amphisomes contribute to presynaptic and long-range signaling in LC neurons, as well as to the timely disposal of intracellular cargo through outsourcing lysosomal degradation to neighbouring neurons. The proposed aims will be achieved through a combination of in vitro cell biological and biochemical assays, viral transgenesis, single-domain antibody-based conformational biosensors, CRISPR-Cas9 technology, in vivo optogenetics, chemogenetics, super-resolution imaging, and in vivo two-photon imaging via a transcranial window.
DFG Programme
Research Units
