The Non-Canonical Role of TERT: A Potential Mechanism for Progesterone- Mediated Neuroprotection After Moderate Traumatic Brain Injury

Abstract

Traumatic brain injury (TBI) is a prevalent cause of death and disability in the United States, affecting an estimated 1.7 million individuals each year. Due to the complexity of the mechanisms underlying brain injury, there is currently no effective, specific treatment for moderating the underlying molecular events that link an injury to the ultimate functional outcome. Recent literature highlights progesterone as a candidate treatment for TBI due to its neurogenerative and neuroprotective properties, but the mechanism by which progesterone imparts neuroprotection remains elusive. Progesterone is thought to regulate telomerase activity (TA), and based on preliminary experiments, we hypothesized that there is an optimal dose of progesterone that maximally increases TA. Canonically, telomerase functions to elongate telomeres, the sequences at the ends of chromosomes that protect genetic information during cell division. However, TERT, the catalytic subunit of telomerase, has also been found to participate in non-canonical roles, including protecting cells from oxidative stress and promoting neuronal survival. We analyzed the effects of different doses of progesterone in naïve, sham injured, and cortically-impacted mice 1 day and 14 days after cortical contusion injury, which mimicked a moderate TBI. Here we report upregulation of TA after treatment with 8 mg/kg of progesterone and suppression of TA after treatment with 32 mg/kg in three distinct brain regions, consistent with the hypothesis that supraoptimal dosages of progesterone could be harmful to neuro-recovery. We also measured telomere length (TL) because shorter TL has been associated with oxidative stress, a result of TBI. TA and TL did not appear to be correlated, suggesting that TBI might trigger the non-canonical neuroprotective activity of telomerase. Our findings support a novel mechanism by which progesterone confers neuroprotection by modulating the activity of TERT, specifically through its non-canonical functions, to attenuate stigmata of TBI.