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

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.

Protein Kinase CK2 and Its Potential Role as a Therapeutic Target in Huntington’s Disease

“…Several HSPs are downregulated in cells and mouse models of HD, which is known to contribute to mtHTT aggregation [ 134 , 149 , 150 ]. HSF1 depletion has also been reported in several cell and mouse models of HD, in human iPSCs derived from patients with HD differentiated into MSN-like cells, and in human postmortem striatum from patients with HD [ 134 , 151 , 152 , 153 , 154 ]. Initial studies proposed that down-regulation of HSPs in HD was facilitated by mtHTT-mediated changes in chromatin remodeling [ 149 ].…”

“…These phosphorylations inactivate HSF1 and allow the recruitment of the E3 ligase Fbxw7, also upregulated in HD, which ubiquitinates HSF1 and signals the protein for proteasomal degradation [ 134 ]. HSF1 degradation leads to decreased expression of several HSF1 targets, including chaperones such as Hsp70 and Hsp25, genes related with GTPase function, and several synaptic proteins [ 134 , 153 , 159 ]. Genetic depletion of CK2α’ via siRNAs in HD cells or gene haploinsufficiency in zQ175 mice (CK2α’ (+/−) ) decreased S303 and S307 phosphorylation, increased HSF1 protein levels and HSPs expression, and subsequently decreased mtHTT aggregation [ 134 ].…”

Kinases and Their Potential as Therapeutic Targets in Huntington’s Disease

“…Several HSPs are downregulated in cells and mouse models of HD, which is known to contribute to mtHTT aggregation [138,153,154]. HSF1 depletion has also been reported in several cell and mouse models of HD, in human iPSCs derived from patienetse with HD differentiated into MSN-like cells, and in human postmortem striatum from pateinets with HD [138,[155][156][157][158]. Initial studies proposed that down-regulation of HSPs in HD was facilitated by mtHTT-mediated changes in chromatin remodeling [153].…”

“…These phosphorylations inactivate HSF1 and allow the recruitment of the E3 ligase Fbxw7, also upregulated in HD, which ubiquitinates HSF1 and signals the protein for proteasomal degradation [138]. HSF1 degradation leads to decreased expression of several HSF1 targets, including chaperones such as Hsp70 and Hsp25, genes related with GTPase function, and several synaptic proteins [138,157,163]. Genetic depletion of CK2α' via siRNAs in HD cells or gene haploinsufficiency in zQ175 mice (CK2α' (+/-) ) decreased S303 and S307 phosphorylation, increased HSF1 protein levels and HSPs expression, and subsequently decreased mtHTT aggregation [138].…”

Inhibitory Effect of Trihydroxy Isoflavone on Neuronal Apoptosis in Natural Aging Rats

“…Aging is a natural and complex process that is inevitable in the organism; neurodegenerative diseases are its main clinical manifestations [1][2][3]. With the intensive research on neurodegenerative diseases associated with brain aging, it has been confirmed that oxidative stress, inflammation, and other induced neuroapoptosis are essential in these diseases [4,5].…”