Yin Yang 1 and guanine quadruplexes protect dopaminergic neurons from cellular stress via transmissive dormancy [YY1 CUT&RUN]

Neurons deploy diverse adaptive strategies to ensure survival and neurotransmission amid cellular stress. Yet, when these adaptive pathways are overwhelmed, functional impairment or neurodegeneration follow. Herein we report a scenario where stressed neurons actively adopt a state of transmissive dormancy, despite rapid activation of stress response pathways, as a terminal protective measure. Examination of dopaminergic neurons surviving severe cellular stress, revealed decreased spontaneous activity accompanied by dynamic control of dopamine metabolism through the Yin Yang 1 (YY1) transcriptional regulator. Under conditions of ionic imbalance or oxidative stress, YY1 promotes expression of the SLC18A2 transporter with the capacity to enhance sequestration of dopamine into transport vesicles. Subsequent DNA damage represses the rate-limiting enzyme in dopamine synthesis, tyrosine hydroxylase (TH), through YY1 mediated stabilization of an intronic guanine quadruplex. This cascade has the potential to drive circuit inactivation and safeguard neurons by minimizing the toxic accumulation of cytosolic dopamine and reducing the energetic expenditure associated with cellular depolarization. In essence, neurons appear to actively prioritize viability over functionality.