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

Nicole Zarate,Luke Carlson,Rocio Gomez-Pastor,Taylor A Intihar,Wei Tsai,Maha Syed,Dahyun Yu,Jacob Sawyer

doi:10.3390/ijms222313113

Abstract

PSD-95 (Dlg4) 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, Hsf1(+/−) 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.

Highlights

The postsynaptic scaffolding protein PSD-95 (Dlg4) is a member of the membraneassociated guanylate kinase (MAGUK) family of proteins known for anchoring ionotropic glutamate receptors (AMPAR and NMDARs) to the membrane
Previous studies showed that Hsf1(+/−) mice compared to WT (HSF1) and PSD-95 decreased in an age-dependent manner in mouse models as well as humans [4,11,33–35], the relationship between the alterations in those proteins has not yet been established
In this study we have demonstrated that the stress protective transcription factor HSF1, known for its role in the regulation of protein quality control machinery and progressively depleted in aging and Huntington’s disease (HD), contributes to the transcriptional regulation of the postsynaptic scaffolding gene Dlg4

Summary

Introduction

The postsynaptic scaffolding protein PSD-95 (Dlg4) is a member of the membraneassociated guanylate kinase (MAGUK) family of proteins known for anchoring ionotropic glutamate receptors (AMPAR and NMDARs) to the membrane. Changes in the levels of PSD-95 alter clustering and maintenance of glutamate receptors, playing an essential role in regulating synaptic transmission and plasticity [1,2]. Glutamatergic synaptic transmission and plasticity are fundamental mechanisms contributing to memory and cognition. Transcriptional dysregulation of PSD-95 has been reported during aging and in several neurodegenerative diseases (NDs) including Alzheimer’s (AD) and Huntington’s disease (HD). Depletion of PSD-95 is believed to contribute to alterations in synaptic function and behavioral deficits [3–6], but the mechanisms involved in the dysregulation of PSD95 under these pathological conditions are not fully understood. Previous studies have identified several transcriptional regulators of Dlg including the Ikaros family zinc finger transcription factor Eos and Early Growth Response 1 (Egr-1) [7–9]. Our understanding of the transcriptional regulation of PSD-95 primarily relies on neurodevelopmental studies where these regulators are expressed in abundance.

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Results

Conclusion