Heat Shock Factor 1 Directly Regulates Postsynaptic Scaffolding PSD-95 in Aging and Huntington's Disease and Influences Striatal Synaptic Density

• Published in: International journal of molecular sciences 2021-12, Vol.22 (23), p.13113
• Main Authors: Zarate, Nicole, Intihar, Taylor A, Yu, Dahyun, Sawyer, Jacob, Tsai, Wei, Syed, Maha, Carlson, Luke, Gomez-Pastor, Rocio
• Format: Article
• Language: English
• Subjects: Aging; Aging - pathology; Aging - physiology; Animals; Cell lines; Cloning; Corpus Striatum - metabolism; Corpus Striatum - pathology; Disease; Disease Models, Animal; Disks Large Homolog 4 Protein - genetics; Disks Large Homolog 4 Protein - metabolism; Female; Gene expression; Gene Expression Regulation; Gene regulation; Genes; Glutamic acid receptors (ionotropic); Heat shock; Heat shock factors; Heat Shock Transcription Factors - genetics; Heat Shock Transcription Factors - metabolism; Homeostasis; HSF1 protein; Humans; Huntington Disease - metabolism; Huntington Disease - pathology; Huntington's disease; Huntingtons disease; Kinases; Male; Memory; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Neostriatum; Neurodegeneration; Neurotransmission; Postsynaptic density proteins; Proof of Concept Study; Proteins; Regulatory sequences; Scaffolding; Synapses; Synapses - pathology; Synaptic density; Transcription factors
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms222313113

PSD-95 ( ) is an ionotropic glutamate receptor scaffolding protein essential in synapse stability and neurotransmission. PSD-95 levels are reduced during aging and in neurodegenerative diseases like Huntington's disease (HD), and it is believed to contribute to synaptic dysfunction and behavioral deficits. However, the mechanism responsible for PSD-95 dysregulation under these conditions is unknown. The Heat Shock transcription Factor 1 (HSF1), canonically known for its role in protein homeostasis, is also depleted in both aging and HD. Synaptic protein levels, including PSD-95, are influenced by alterations in HSF1 levels and activity, but the direct regulatory relationship between PSD-95 and HSF1 has yet to be determined. Here, we showed that HSF1 chronic or acute reduction in cell lines and mice decreased PSD-95 expression. Furthermore, mice had reduced PSD-95 synaptic puncta that paralleled a loss in thalamo-striatal excitatory synapses, an important circuit disrupted early in HD. We demonstrated that HSF1 binds to regulatory elements present in the PSD-95 gene and directly regulates PSD-95 expression. HSF1 DNA-binding on the PSD-95 gene was disrupted in an age-dependent manner in WT mice and worsened in HD cells and mice, leading to reduced PSD-95 levels. These results demonstrate a direct role of HSF1 in synaptic gene regulation that has important implications in synapse maintenance in basal and pathological conditions.