| Popis: |
Autophagy is an evolutionarily conserved process that serves to provide nutrients during starvation and to eliminate detrimental cellular components like dysfunctional organelles and damaged proteins. This role of autophagy might be critical in neurons because of their postmitotic nature. However, accumulating evidence indicates that autophagy is not merely a housekeeping process. The study shows that the crucial AuTophaGy protein ATG5 functions in neurons to regulate the cAMP-dependent protein kinase A (PKA)-mediated phosphorylation of synapse-confined proteome. This function of ATG5 is independent of bulk degradation of synaptic proteins and requires the starvation-induced targeting of PKA regulatory subunit type 1 (R1) to neuronal autophagosomes. Loss of ATG5 in either excitatory or inhibitory neurons causes a drastic accumulation of PKA R1 at synapses, which sequesters the PKA catalytic subunit and causes cAMP-dependent remodelling of the synaptic phosphoproteome. Autophagy-deficient excitatory synapses are characterized by increased thickness of the postsynaptic density and alterations in AMPA receptor GLUR1 trafficking, a phenotype that results in augmented excitatory neurotransmission and appearance of seizures in mice with glutamatergic forebrain-confined ATG5 deletion. My work has identified a previously unknown role of neuronal autophagy in regulating PKA-dependent signalling at glutamatergic synapses and suggest PKA as a target for treating autophagy-associated neurodegenerative diseases. |
