@misc{Gbadamosi_Ismail_TDP-43-metabolism_2025,
 author={Gbadamosi, Ismail},
 editor={Kaczmarek, Leszek (1957– ) : Supervisor},
 editor={Jawaid, Ali : Auxiliary supervisor},
 copyright={Rights Reserved - Free Access},
 address={Warsaw},
 howpublished={online},
 year={2025},
 school={Nencki Institute of Experimental Biology PAS},
 school={degree obtained: 2026},
 publisher={Nencki Institute of Experimental Biology PAS},
 language={eng},
 abstract={Cytoplasmic aggregation and nuclear depletion of TAR DNA-binding protein 43 (TDP-43) represent key pathological features in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Since TDP-43 is a critical regulator of RNA processing and metabolism, its dysfunction contributes to cellular stress through both loss- and gain-of-function mechanisms. Interestingly, metabolic conditions commonly linked to poor systemic health, including type 2 diabetes mellitus (T2DM), dyslipidemia, and elevated body mass index (BMI), are associated with prolonged survival in ALS. Conversely, high levels of physical activity have been linked to increased ALS risk, suggesting a complex interplay between metabolism and TDP-43- mediated neurodegeneration. This study systematically investigates the impact of TDP-43 dysfunction—via knockdown or M337V mutation—on cellular energy metabolism and metabolic sensing, with a focus on motor neuron vulnerability. Using NSC34 motor neuron-like cells, TDP-43 knockdown induced a hypermetabolic state characterized by increased glycolysis, oxidative phosphorylation, and ATP production, accompanied by persistent activation of AMP-activated protein kinase (AMPK). In contrast, mutant TDP-43 disrupted AMPK regulation primarily under metabolic stress, leading to prolonged AMPK activation during recovery phases. Comparative analyses in BV2 microglia and N2A neuroblastoma cells highlighted distinct cell-specific metabolic responses to TDP-43 perturbation. To explore how systemic metabolic status influences TDP-43–associated metabolic changes, we treated TDP-43–deficient NSC34 motor neuron–like cells with serum from mice subjected to voluntary exercise (VE) or a high-fat diet (HFD), revealing a sex-dependent modulation of those metabolic alterations. Female-derived serum more strongly regulated glycolytic and mitochondrial responses in both motor neurons and microglia. Finally, integration of patient-derived transcriptomic datasets from ALS and FTLD postmortem tissues with NSC34 RNA-seq data identified both common and disease-specific metabolic dysregulation. ALS transcriptomes were enriched for lipid metabolism and insulin signaling pathways, while FTLD transcriptomes showed predominant alterations in RNA processing and translation. Collectively, these findings demonstrate that TDP-43 dysfunction disrupts cellular metabolism in a cell-type- and context-dependent manner, with motor neurons displaying heightened vulnerability. The data further suggest that systemic metabolic states modulate TDP-43-driven metabolic stress, providing insights into potential metabolic targets for therapeutic intervention in ALS and FTLD.},
 title={TDP-43-metabolism interplay in neurodegenerative disorders : PhD thesis},
 type={Text},
 URL={http://www.rcin.org.pl/Content/248047/WA488_285013_20888_Gbadamosi-Ismail-2025.pdf},
 keywords={Amyotrophic lateral sclerosis, AMPK, Energy metabolism, Frontotemporal lobar degeneration, Motor neurons, Metabolic sensing, Systemic metabolism, TDP-43},
}