INTRODUCTION: TDP-43 mislocalization and nuclear loss are early hallmarks of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Paradoxically, patients with systemic metabolic disorders—such as type 2 diabetes and dyslipidemia—often exhibit slower ALS/FTD progression, suggesting that conventionally “risky” metabolic profiles may modulate TDP-43–driven neurodegeneration.

AIM(S): To delineate cell-specific bioenergetic effects of TDP-43 loss of function in motor neurons, neuronal cells, and microglia, and thereby uncover mechanisms underlying selective motor neuron vulnerability in ALS/FTD.

METHOD(S): TDP-43 was silenced by siRNA in NSC-34 motor neurons, N2A neuroblastoma cells, and BV2 microglia, with knockdown confirmed by Western blot. Twenty-four hours post-transfection, glycolytic flux (extracellular acidification rate) and mitochondrial respiration (oxygen consumption rate) were measured using a Seahorse XF Analyzer. AMP-activated protein kinase (AMPK) activation was evaluated via Thr172 phosphorylation

RESULTS: In NSC-34 motor neurons, TDP-43 depletion induced concurrent increases in glycolysis and oxidative phosphorylation, defining a hypermetabolic phenotype. N2A cells exhibited reduced glycolytic and respiratory rates (hypometabolic), whereas BV2 microglia shifted toward predominantly glycolytic metabolism without altering respiration. Strikingly, only motor neurons showed elevated AMPK phosphorylation, implicating dysregulated energy sensing as a key driver of their selective vulnerability.

CONCLUSIONS: TDP-43 loss triggers cell-autonomous bioenergetic reprogramming: hypermetabolism with AMPK dysregulation in motor neurons versus divergent metabolic shifts in neuronal and glial lines. This mismatch may underlie selective motor neuron degeneration in ALS/FTD. Targeting AMPK pathways—and validating these findings in vivo—could yield novel neuroprotective strategies.

FINANCIAL SUPPORT: This study is supported by FNP and JPND