Theophylline as a Potential Therapeutic Candidate for TDP-43 Proteinopathies

The cytoplasmic aggregates of the TAR DNA-binding protein 43 (TDP-43) are a pathogenic hallmark of some neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and limbic-predominant age-related TDP-43 encephalopathy (LATE). Overexpression of TDP-43 induces cytoplasmic accumulation of TDP-43, leading to mitochondrial dysfunction and cell death. Theophylline treatment significantly decreased accumulation of cytoplasmic TDP-43 and cell death in the TDP-43 overexpressing human neuronal cell lines SH-SY5Y. TDP-43-induced eIF2α phosphorylation is also attenuated by theophylline treatment. Additionally, theophylline alleviated mitochondrial dysfunction caused by TDP-43 overexpression, restoring key mitochondrial respiration parameters such as basal and maximal respiration rates and ATP production. Moreover, Dietary supplementation with theophylline substantially improved both longevity and motility in Drosophila models expressing TDP-43 in neurons. Taken together, these findings suggest that theophylline may be a potential therapeutic candidate for TDP-43 proteinopathies.