Disrupted TFEB/GDNF–cAMP/ATP Coupling Underlies Astrocytic Dysfunction and Depression in LRRK2 G2019S Parkinson's Mice

The LRRK2 G2019S mutation, a Parkinson's disease-linked variant, has been associated with depression-like phenotypes, but mechanisms remain unclear. We chart age-dependent behavioral changes and astrocyte reactivity in G2019S mice and define a pathway connecting LRRK2 to TFEB/GDNF signaling, cellular energetics, and inflammation. From ∼25 weeks, G2019S carriers show robust depressive-like behaviors with reduced hippocampal GDNF, exaggerated astrocytic inflammation, diminished ATP, and increased neuronal apoptosis; pharmacologic LRRK2 kinase inhibition reverses these abnormalities. Single-cell transcriptomics identifies 507 differentially expressed genes enriched for adenylyl cyclase/cAMP signaling, oxidative phosphorylation/ATP metabolism, calcium/ion homeostasis, and cytokine pathways, indicating disrupted cAMP-ATP coupling and perturbed neuroimmune signaling. Mechanistically, LRRK2 G2019S binds and suppresses TFEB while elevating Ser211 phosphorylation, lowering astrocytic GDNF, amplifying inflammation, and reducing ATP. Critically, TFEB overexpression restores GDNF, elevates astrocytic ATP, attenuates inflammatory mediators, and improves depressive-like behaviors. Enhancing effector nodes is therapeutic: bilateral hippocampal forskolin rapidly (within 6 h) raises cAMP and reverses multiple behavioral measures, and ATP supplementation (systemic or hippocampal) yields comparable benefits. These findings position a LRRK2→TFEB/GDNF→cAMP/ATP axis as a driver of astrocytic inflammation and energetic imbalance underlying depression in G2019S mice and highlight convergent therapeutic strategies targeting LRRK2, TFEB, and ATP/cAMP.