Biology subjects

Rodgers, B.

Publications and source records attributed to Rodgers, B..

3 recordsLinked to original sources

bioRxiv2025

Alpha-synuclein overexpression without vocalization deficits in a mouse model of parkinsonism.

Voice deficits are common in Parkinsons disease (PD) and significantly impact quality of life by increasing stress, social isolation, and caregiver burden. However, despite this impact, there are currently no treatments that target the underlying pathophysiology of PD in the vocalization system. The goal of this study was to examine the effect of one possible underlying mechanism responsible for the complex voice deficits that exist in PD; overexpression of the protein alpha-synuclein. Results show that overexpression of alpha-synuclein, prior to the development of alpha-synuclein aggregate pathology, does not result in significant vocalization deficits. A small but statistically significant increase in the total number of complex vocalizations was found in mice overexpressing alpha-synuclein compared to wildtype mice, but there were no differences in complexity ratio or any of the other specific vocalization parameters tested. Results provide a critical foundational understanding of the impact of overexpression versus aggregation of alpha-synuclein on voice deficits in PD. Future work will focus on manipulation of alpha-synuclein aggregate pathology, and not overexpression alone, to reduce or eliminate the burden of PD specific voice disorders. Summary StatementThis study shows that overexpression of alpha-synuclein alone does not result in significant vocalization deficits, indicating that alpha-synuclein aggregate pathology within the vocalization system is required to induce vocalization deficits.

neuroscience↗

bioRxiv2024

DNA methylation protects cancer cells against non-canonical senescence

Inhibitors of DNA methylation such as 5-aza-deoxycytidine are widely used in experimental and clinical settings. However, their mechanism of action is such that DNA damage inevitably co-occurs with loss of DNA methylation, making it challenging to discern their respective effects. Here we deconvolute the effects of decreased DNA methylation and DNA damage on cancer cells, by using degron alleles of key DNA methylation regulators. We report that cancer cells with decreased DNA methylation --but no DNA damage-- enter cellular senescence, with G1 arrest, SASP expression, and SA-{beta}-gal positivity. This senescence is independent of p53 and Rb, but involves p21, which is cytoplasmic and inhibits apoptosis, and cGAS, playing a STING-independent role in the nucleus. Xenograft experiments show that tumor cells can be made senescent in vivo by decreasing DNA methylation. These findings reveal the intrinsic effects of loss of DNA methylation in cancer cells and have practical implications for future therapeutic approaches.

molecular biology↗

bioRxiv2023

Non-canonical functions of UHRF1 maintain DNA methylation homeostasis in cancer cells

DNA methylation is an essential epigenetic chromatin modification, and its maintenance in mammals requires the protein UHRF1. It is yet unclear if UHRF1 functions solely by stimulating DNA methylation maintenance by DNMT1, or if it has important additional functions. Using degron alleles, we show that UHRF1 depletion causes a much greater loss of DNA methylation than DNMT1 depletion. This is not caused by passive demethylation as UHRF1-depleted cells proliferate more slowly than DNMT1-depleted cells. Instead, bioinformatics, proteomics and genetics experiments establish that UHRF1, besides activating DNMT1, interacts with DNMT3A and DNMT3B and promotes their activity. In addition, we show that UHRF1 antagonizes active DNA demethylation by TET2. Therefore, UHRF1 has non-canonical roles that contribute importantly to DNA methylation homeostasis; these findings have practical implications for epigenetics in health and disease.

molecular biology↗