Browsing by Subject "Synapse impairment"

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    Mechanisms and consequences of the HSF1 degradation pathway in Huntington's disease
    (2022-07) Zarate, Nicole
    Huntington’s disease (HD) is a fatal autosomal dominant neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in exon 1 of the huntingtin gene (HTT). HD is characterized by progressive motor, cognitive, and psychiatric impairments for which there is no cure. Medium spiny neurons (MSNs) of the striatum are preferentially affected by the mutant huntingtin protein (mtHTT) and are subject to neuronal dysfunction and eventual cell death. One driver believed to contribute to MSN dysfunction in HD is excitatory synapse impairment. Deficits in excitatory synapses can range from loss of overall synaptic input to MSNs, loss of synaptic proteins, and transcriptional changes in genes necessary for synaptic stability. However, the mechanisms behind excitatory synapse instability in HD are largely unknown. In this thesis, the role of the stress protective transcription factor, Heat shock factor 1 (HSF1) in excitatory synapse impairment in HD is extensively explored. We show that induction of the tumor suppressor p53 directly binds and regulates expression of Protein Kinase CK2α’, a kinase that was previously demonstrated to phosphorylate HSF1 and lead to its eventual degradation. Reductions in p53 and CK2α’ rescue levels of HSF1 in MSNs, improves expression of HSF1 target genes, and improves levels of T-S synapses in zQ175 HD mice. Further characterization of CK2α’ knockdown in zQ175 HD mice shows that rescued levels of HSF1 parallel improvements in motor behavior, transcriptional deficits associated with synaptic stability, and impairments in synaptic transmission. Given the parallels in improved HSF1 levels and improvements in various synaptic deficits, we next investigated if HSF1 was playing a direct role in excitatory synapse regulation. We demonstrated HSF1 directly regulates the expression of PSD-95 (Dlg4), a protein that participates in stabilizing excitatory synapses, and progressive loss of HSF1 in HD contributes to PSD-95-dependent depletion of excitatory synapse density. Circuit-specific synaptic deficits are reported in HD with an early loss of thalamo-striatal (T-S) synapses followed by changes in cortico-striatal (C-S) synapses at later stages in disease. We showed aged mice lacking one allele of Hsf1(Hsf1(+/-)) presented reduced PSD-95 and T-S synapse levels, indicating HSF1 could play an essential role in the stability of T-S synapses. However, analyses in younger mice showed Hsf1 haploinsufficiency does not significantly influence levels of T-S synapses. Pilot studies using ChIP-seq however indicate genome-wide enrichment of HSF1 binding to genes associated with synapse stability in young mice, other than PSD-95, revealing new potential HSF1 targets that could contribute to synapse dysfunction in HD at different disease stages. Contrarily, acute reduction of HSF1 in the adult striatum using adeno-associated viruses, similar to HSF1 progressive depletion in HD, has negative effects on aspects of striatal function such as MSN protein levels and spatial recognition cognitive behavior. We concluded that HSF1 plays a time-sensitive bimodal role in striatal physiology with an enhanced protective role in the aged brain. Lastly, we demonstrated through in vivo longitudinal analyses of brain neurochemicals, measured by proton magnetic resonance spectroscopy (1H-MRS), that specific neurochemical changes correlate with progressive alterations in T-S and C-S synapses during HD. In addition, CK2α’ knock down and subsequent HSF1 rescue can improve some of these neurochemical alterations. Therefore, these neurochemical measures can be used to monitor circuit dependent synaptic changes. This provides a potential tool for monitoring excitatory synaptic changes in vivo with surrogate biomarkers using MRS. In conclusion, this dissertation provides a holistic view of the mechanisms involved in HSF1 degradation in HD and the pathophysiological roles of this transcription factor in synapse stability. Results from these studies demonstrate how targeting aspects of the HSF1 degradation pathway could be a potential therapeutic avenue in treating HD.