Biology subjects

Ickert, L.

Publications and source records attributed to Ickert, L..

3 recordsLinked to original sources

bioRxiv2025

Nutrient stress activates Rab5b-mediated autophagy to remodel the synaptic proteome

Synaptic proteostasis is crucial for maintaining neuronal function and plasticity, yet how synapses adapt to metabolic stress remains poorly understood. Here, we show that nutrient deprivation, particularly serum withdrawal, induces robust autophagy-dependent remodeling of the synaptic proteome, while mTORC1 inhibition has more limited effects. Nutrient stress rapidly activates autophagy both globally and at synapses, with synaptic autophagy peaking within 1-2 hours of serum withdrawal. Mechanistically, we uncover that the LC3 lipidation complex (ATG5-ATG12-ATG16L1) is recruited to synapses via Rab5b-positive endosomes in a dynein-dependent manner. Live imaging reveals enhanced Rab5b-ATG16L1 co-trafficking and increased ATG5 mobility upon serum withdrawal, supporting a model of spatiotemporally controlled autophagy precursor delivery to synaptic compartments. Functionally, nutrient deprivation acutely dampens neuronal excitability in vitro, while a two-week fasting-mimicking diet in vivo triggers synaptic proteome remodeling that overlaps with starvation-induced autophagy cargo. In contrast, restriction of mTORC1-activating amino acids fails to induce comparable synaptic changes, suggesting that synaptic autophagy is regulated by nutrient signals beyond mTORC1. Our findings define a Rab5b-mediated trafficking mechanism that couples nutrient sensing to localized synaptic degradation, providing new insight into how neurons preserve proteostasis under metabolic challenge.

neuroscience↗

bioRxiv2024

Autophagy regulator ATG5 preserves cerebellar function by safeguarding its glycolytic activity

Dysfunctions in autophagy, a highly conserved cellular mechanism responsible for the degradation of intracellular components within lysosomes, often result in neurodegeneration. The neuroprotective effect of autophagy varies across neuronal subtypes, and the mechanisms of selective vulnerability of neurons to autophagy dysfunction are currently unknown. Utilizing a mouse model of ATG5 deficiency in inhibitory neurons and a comprehensive approach, including PET imaging, metabolomics, stable-isotope labeling studies, and live cell imaging, we establish that autophagy contributes to the survival of cerebellar Purkinje cells (PCs) by safeguarding their glycolytic activity. We show that the core autophagy protein ATG5 downregulates the levels of the glucose transporter 2 (GLUT2) during brain maturation. Autophagy-deficient PCs exhibit increased glucose uptake, along with elevated levels of glycolytic intermediates and methylglyoxal-modified proteins. We propose lysophosphatidic acid and serine as glycolytic intermediates inducing PC death and demonstrate that deletion of GLUT2 in ATG5-deficient mice mitigates PC neurodegeneration and restores their ataxic gait. Taken together, this study reveals a novel neuroprotective role of autophagy in preventing excessive glycolytic metabolism in the brain.

neuroscience↗

bioRxiv2022

Autophagy regulates neuronal excitability by controlling cAMP/Protein Kinase A signaling

Autophagy provides nutrients during starvation and eliminates detrimental cellular components. However, accumulating evidence indicates that autophagy is not merely a housekeeping process. Here, we show that the protein AuTophaGy 5 (ATG5) functions in neurons to regulate the cAMP-dependent protein kinase A (PKA)-mediated phosphorylation of a synapse-confined proteome. This function of ATG5 is independent of bulk turnover of synaptic proteins and requires the targeting of PKA inhibitory R1 subunits to autophagosomes. Neuronal loss of ATG5 causes synaptic accumulation of PKA R1, which sequesters the PKA catalytic subunit and diminishes the cAMP/PKA-dependent phosphorylation of postsynaptic cytoskeletal proteins mediating AMPAR trafficking. Glutamatergic neurons-confined ATG5 deletion augments AMPAR-dependent excitatory neurotransmission and causes the appearance of spontaneous recurrent seizures in mice. Our findings identify a novel role of autophagy in regulating PKA signaling at glutamatergic synapses and suggest the PKA as a target for restoration of synaptic function in neurodegenerative conditions with autophagy dysfunction.

neuroscience↗