TDP-43 DYSFUNCTION DRIVES CELL-TYPE-SPECIFIC METABOLIC REPROGRAMMING IN MOTOR NEURONS AND MICROGLIA

TDP-43 nuclear depletion and cytoplasmic mislocalization are defining molecular features of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Epidemiological evidence points to critical roles for metabolic cascades in ALS and PTLD pathogenesis, yet the role of TDP-43 in regulating brain energy metabolism remains unclear. We aimed to examine the effects of TDP-43 dysfunction on motor neuronal and microglial metabolism and its functional consequences for neuronal health. TDP-43 was depleted in mouse motor neuron- and microglia-like cells using RNA interference, followed by assessment of glycolytic flux, mitochondrial oxidative phosphorylation (OXPHOS), and cellular energy sensing. TDP-43 loss induced divergent metabolic remodeling in a cell-type-specific manner. In motor neurons, TDP-43 depletion triggered a hypermetabolic state characterized by coordinated upregulation of glycolysis and mitochondrial OXPHOS, accompanied by impaired AMPK signalling, leading to sustained energetic demand. In contrast, microglia underwent a pronounced shift toward glycolysis without a corresponding increase in mitochondrial OXPHOS. This glycolytic reprogramming was functionally consequential, promoting exaggerated engulfment of healthy synaptoneurosomes. Importantly, bypassing glycolysis rescued the enhanced engulfment phenotype, supporting the notion that altered energy metabolism is a causal driver of pathological microglial behavior. Collectively, these findings identify TDP-43 dysfunction as a driver of cell-type-specific metabolic rewiring, coupling neuronal hypermetabolism and impaired energy sensing with microglial glycolytic activation and maladaptive synaptic pruning. This neuron–microglia metabolic mismatch provides a mechanistic pathway by which TDP-43 pathology can cause both motor neuron stress and non-cell-autonomous synaptic injury, highlighting energy metabolism as a tractable therapeutic axis in ALS and FTD.