Heat Shock Factor 1 directly regulates postsynaptic scaffolding PSD-95 and controls

PSD-95 (Dlg4) is an ionotropic glutamate receptor scaffolding protein essential in 12 synapse stability and neurotransmission. PSD-95 levels are reduced during aging and in 13 neurodegenerative diseases like Huntington’s disease (HD), and it is believed to contrib14 ute to synaptic dysfunction and behavioral deficits. However, the mechanism responsible 15 for PSD-95 dysregulation under these conditions is unknown. The Heat Shock transcrip16 tion Factor 1 (HSF1), canonically known for its role in protein homeostasis, is also depleted 17 in both aging and HD. Synaptic protein levels, including PSD-95, are influenced by alter18 ations in HSF1 levels and activity, but the direct regulatory relationship between PSD-95 19 and HSF1 has yet to be determined. Here, we showed that HSF1 chronic or acute depletion 20 in cell lines and mice decreased PSD-95 expression. Furthermore, HSF1(+/-) mice had re21 duced PSD-95 synaptic puncta that paralleled a loss in thalamo-striatal excitatory synap22 ses, an important circuit disrupted early in HD. We demonstrated that HSF1 binds to reg23 ulatory elements present in the PSD-95 gene and directly regulates PSD-95 expression. 24 HSF1 DNA-binding on the PSD-95 gene was disrupted in an age-dependent manner in 25 WT mice and worsened in HD cells and mice, leading to reduced PSD-95 levels. These 26 results demonstrate a direct role of HSF1 in synaptic gene regulation that has important 27 implications in synapse maintenance in basal and pathological conditions. 28