Explore the vast range of titles available.

Heat shock factor 1 (HSF1) is a stress-protective transcription factor most associated with transcriptional regulation of genes involved thermal stress response and protein folding. The canonical activation cycle of HSF1, in which HSF1 recognizes a simple promoter binding site known as a heat shock element (HSE) to promote the transcription of molecular chaperones, has been well documented. However, it is now evident that mammalian HSF1 exhibits unexpected complexity and participates in the response to a vast array of cellular stress types. The versatility of HSF1 can be attributed to distinct local protein concentrations, posttranslational modifications (PTMs), and binding partners found in different anatomical regions of the mammalian system. Advances in our knowledge of HSF1 under different types of stress have illuminated its vast array of gene targets, ranging from protein folding to mitochondrial homeostasis to cytoskeletal stability and beyond. In this review, we explore current knowledge of mammalian HSF1 and its gene targets within the central nervous system. While HSF1 has been extensively studied in the context of neurodegeneration, our understanding of its diverse roles in this setting remains limited. We also highlight emerging evidence supporting a physiological role for HSF1 in the healthy brain, an area that has received relatively little attention. Advancing a more comprehensive understanding of HSF1 function in the mammalian brain may aid in the development of novel therapeutics aimed at alleviating symptoms across a range of neurological disorders.

Introduction Amyloid‐beta oligomers (AβOs) accumulate in Alzheimer's disease and may instigate neuronal pathology and cognitive impairment. We examined the ability of a new probe for molecular magnetic resonance imaging (MRI) to detect AβOs in vivo, and we tested the behavioral impact of AβOs injected in rabbits, a species with an amino acid sequence that is nearly identical to the human sequence. Methods Intracerebroventricular (ICV) injection with stabilized AβOs was performed. Rabbits were probed for AβO accumulation using ACUMNS (an AβO‐selective antibody [ACU193] coupled to magnetic nanostructures). Immunohistochemistry was used to verify AβO presence. Cognitive impairment was evaluated using object location and object recognition memory tests and trace eyeblink conditioning. Results AβOs in the entorhinal cortex of ICV‐injected animals were detected by MRI and confirmed by immunohistochemistry. Injections of AβOs also impaired hippocampal‐dependent, but not hippocampal‐independent, tasks and the area fraction of bound ACUMNs correlated with the behavioral impairment. Discussion Accumulation of AβOs can be visualized in vivo by MRI of ACUMNS and the cognitive impairment induced by the AβOs can be followed longitudinally with the novel location memory test.

Heat shock factor 1 (HSF1) is a stress-protective transcription factor most associated with transcriptional regulation of genes involved thermal stress response and protein folding. The canonical activation cycle of HSF1, in which HSF1 recognizes a simple promoter binding site known as a heat shock element (HSE) to promote the transcription of molecular chaperones, has been well documented. However, it is now evident that mammalian HSF1 exhibits unexpected complexity and participates in the response to a vast array of cellular stress types. The versatility of HSF1 can be attributed to distinct local protein concentrations, posttranslational modifications (PTMs), and binding partners found in different anatomical regions of the mammalian system. Advances in our knowledge of HSF1 under different types of stress have illuminated its vast array of gene targets, ranging from protein folding to mitochondrial homeostasis to cytoskeletal stability and beyond. In this review, we explore current knowledge of mammalian HSF1 and its gene targets within the central nervous system. While HSF1 has been extensively studied in the context of neurodegeneration, our understanding of its diverse roles in this setting remains limited. We also highlight emerging evidence supporting a physiological role for HSF1 in the healthy brain, an area that has received relatively little attention. Advancing a more comprehensive understanding of HSF1 function in the mammalian brain may aid in the development of novel therapeutics aimed at alleviating symptoms across a range of neurological disorders.

Huntington's disease (HD) is a devastating autosomal dominant neurodegenerative disease that manifests with progressive motor, cognitive, and psychological impairments. HD is caused by a polyQ (CAG) repeat expansion in the huntingtin ( ) gene, leading to the misfolding and aggregation of mutant HTT protein (mHTT) and the preferential degeneration of the striatum. Previously in our lab, we identified Protein Kinase CK2 as an important kinase involved in the pathophysiology of HD. Specifically, the alpha prime catalytic subunit of CK2 (CK2α') is upregulated in HD, and genetic depletion of CK2α' in HD mice results in improved motor behavior, decreased mutant Htt aggregation, and improved neuronal function. Silmitasertib (CX-4945) is an FDA designated orphan drug that inhibits CK2. This study aims to investigate whether CX-4945 treatment ameliorates HD pathology. We treated prodromal and late symptomatic HD mice, and used a variety of immunohistochemical, biochemical, physiological and behavioral approaches. We found that CX-4945 presented benefits in the amelioration of HD pathophysiology in both treated groups. Importantly, we found CX-4945 decreased mHtt aggregation, increased DARPP-32 expression and excitatory synapse density, restored homeostatic astrocyte phenotypes and ameliorated neuroinflammation and microgliosis, altogether resulting in improved motor behavior. These results support CX-4945 as a strong candidate for a targeted therapy to treat HD.

Huntington's disease (HD) is a neurodegenerative disease resulting in devastating motor, cognitive, and psychiatric deficits. The striatum is a brain region that controls movement and some forms of cognition and is most significantly impacted in HD. However, despite well-documented deficits in learning and memory in HD, knowledge of the potential implication of other brain regions such as the hippocampus remains limited. Here, we study the comparative impact of enhanced mHTT aggregation and neuropathology in the striatum and hippocampus of two HD mouse models. We utilized the zQ175 as a control HD mouse model and the Q175DN mice lacking the PGK-Neomycin cassette generated in house. We performed a comparative characterization of the neuropathology between zQ175 and Q175DN mice in the striatum and the hippocampus by assessing HTT aggregation, neuronal and glial pathology, chaperone expression, and synaptic density. We showed that Q175DN mice presented enhanced mHTT aggregation in both striatum and hippocampus compared to zQ175. Striatal neurons showed a greater susceptibility to enhanced accumulation of mHTT than hippocampal neurons in Q175DN despite high levels of mHTT in both regions. Contrary to the pathology seen in the striatum, Q175DN hippocampus presented enhanced spare capacity showing increased synaptic density, decreased Iba1 microglia density and enhanced HSF1 levels in specific subregions of the hippocampus compared to zQ175. Q175DN mice are a valuable tool to understand the fundamental susceptibility differences to mHTT toxicity between striatal neurons and other neuronal subtypes. Furthermore, our findings also suggest that cognitive deficits observed in HD animals might arise from either striatum dysfunction or other regions involved in cognitive processes but not from hippocampal degeneration.

Tauopathies are a group of neurodegenerative diseases characterized by tau accumulation, neuroinflammation, and synaptic dysfunction, yet effective treatments remain elusive. Protein Kinase CK2 has been previously associated with different aspects of tau pathology but genetic evidence for the contribution of CK2 to tauopathy remained lacking. Here, we show CK2α', one of the two catalytic subunits of CK2, as a novel regulator of tau-mediated neurodegeneration. We found that CK2α' expression is elevated in postmortem brains of dementia patients and in the hippocampus of PS19 tauopathy mice, especially in neurons and microglia. Using genetic haploinsufficiency in PS19 mice, we demonstrated that reduced CK2α' levels significantly decrease phosphorylated tau and total tau burden in the hippocampus and cortex. CK2α' depletion also attenuated microglial activation, pro-inflammatory cytokine production, and microglia synaptic engulfment, enhanced synaptic gene expression, synaptic density, and LTP. Importantly, CK2α' depletion rescued cognitive deficits assessed in the Barnes maze. These effects appear to be mediated through both neuronal and glial functions and may involve CK2α'-dependent modulation of tau-associated phosphorylation and neuroinflammatory and immune signaling pathways.