Biology subjects

Zarate, N.

Publications and source records attributed to Zarate, N..

5 recordsLinked to original sources

bioRxiv2026

HSF1 controls transcriptional programs that establish thalamostriatal shaft synaptic architecture and preserve cognitive flexibility

Cognitive flexibility (CF) declines during aging and is further impaired in neurodegenerative diseases such as Huntingtons disease (HD), yet the molecular mechanisms underlying these deficits remain poorly understood. Thalamostriatal (T-S) synapses are critical for CF, and we previously identified Heat Shock Factor 1 (HSF1) as a regulator of T-S density in HD. However, how HSF1 regulates T-S synapses and whether it modulates cognitive flexibility (CF) remained unclear. Here, we combined HSF1 ChIP-seq, transcriptomics, synapto-proteomics, targeted genetic manipulations and behavioral analyses to study how HSF1 regulates T-S synapses and CF. We found HSF1 directly controls a transcriptional program governing postsynaptic architecture and actin cytoskeletal dynamics, which are disrupted in aging and HD. Loss of HSF1 drives selective destabilization of actin patches at T-S shaft synapses and impaired CF decline. Our results underscore a novel function for HSF1 in the regulation of striatal neural circuits with essential implications in the neurobiology of cognitive flexibility.

neuroscience↗

bioRxiv2021

Striatal compartmentalization and clustering of different subtypes of astrocytes is altered in the zQ175 Huntington's disease mouse model

Huntingtons disease (HD) is a devastating neurodegenerative disease that primarily affects the striatum, a brain region that controls movement and some forms of cognition. Dysfunction and loss of medium spiny neurons of the striatum is accompanied by astrogliosis (increased astrocyte density and pathology). For decades, astrocytes were considered a homogeneous cell type, but recent transcriptomic analyses revealed astrocytes are a heterogeneous population classified into multiple subtypes depending on the expression of different gene markers. Here, we studied whether three different striatal astrocyte subtypes expressing glutamine synthetase (GS), glial fibrillary acidic protein (GFAP), or S100 calcium-binding protein B (S100B) are differentially altered in HD. We conducted a comparative immunofluorescence analysis in the striatum of WT and the heterozygous zQ175 HD mouse model and found that the expression and abundance of GFAP+ and S100B+ astrocytes increased in zQ175 mice, while GS+ astrocytes showed no alteration. We then explored whether there was a differential spatial distribution of any of these subtypes within the striatum. We developed a systematic brain compartmentalization approach and found that while GS+ and S100B+ astrocytes were more homogeneously distributed throughout the striatum in zQ175 mice, GFAP+ astrocytes preferentially accumulated in the dorsomedial and dorsolateral striatum, which are regions associated with goal-directed and habitual behaviors. Additionally, GFAP+ astrocytes in zQ175 mice showed increased clustering, a parameter that indicates increased proximity and that is associated with localized inflammation and/or neurodegeneration. Our data suggest a differential susceptibility in both increased density and striatal compartmentalization of different subtypes of astrocytes in zQ175. These results highlight new potential implications for our understanding of astrocyte pathology in HD.

neuroscience↗

bioRxiv2021

In vivo MR spectroscopy reflects synapse density in a Huntington's disease mouse model

Striatal medium spiny neurons are highly susceptible in Huntingtons disease (HD), resulting in progressive synaptic perturbations that lead to neuronal dysfunction and death. Non-invasive imaging techniques, such as proton magnetic resonance spectroscopy (1H-MRS), are used in HD mouse models and patients with HD to monitor neurochemical changes associated with neuronal health. However, the association between brain neurochemical alterations and synaptic dysregulation is unknown, limiting our ability to monitor potential treatments that may affect synapse function. We conducted in vivo longitudinal 1H-MRS in the striatum followed by ex-vivo analyses of excitatory synapse density of two synaptic circuits disrupted in HD, thalamo-striatal (T-S) and cortico-striatal (C-S) pathways, to assess the relationship between neurochemical alterations and changes in synapse density. We used the zQ175(Tg/0) HD mouse model as well as zQ175 mice lacking one allele of CK2(zQ175(Tg/0):CK2(+/-)), a kinase previously shown to regulate synapse function in HD. Longitudinal analyses of excitatory synapse density showed early and sustained reduction in T-S synapses in zQ175 mice, preceding C-S synapse depletion, which was rescued in zQ175:CK2(+/-). Changes in T-S and C-S synapses were accompanied by progressive alterations in numerous neurochemicals between WT and HD mice. Linear regression analyses showed C-S synapse number positively correlated with 1H-MRS-measured levels of GABA while T-S synapse number positively correlated with levels of alanine, phosphoethanolamine and lactate, and negatively correlated with total creatine levels. These associations suggest that these neurochemical concentrations measured by 1H-MRS may facilitate monitoring circuit-specific synaptic dysfunction in the zQ175 mouse model and in other HD pre-clinical studies. Significance StatementThe pathogenic events of many neurodegenerative diseases including HD are triggered by reductions in number of synapses. Therefore, in vivo measures that reflect synapse number represent a powerful tool to monitor synaptic changes in numerous brain disorders. In this study, we showed that non-invasive in vivo 1H-MRS reflects excitatory synapse number in the striatum of the zQ175 mouse model of HD. The combination of longitudinal 1H-MRS and immunofluorescence synapse detection revealed that distinct neurochemical levels significantly correlated with different striatal glutamatergic synaptic input pathways, suggesting that 1H-MRS could distinguish circuit-dependent synapse changes in HD. These results provide potential neurochemical biomarkers to monitor synaptic changes in future pre-clinical trials with HD models.

neuroscience↗

bioRxiv2020

Protein kinase CK2 alpha prime and alpha-synuclein constitute a key regulatory pathway in Huntington's disease

BackgroundHuntingtons Disease (HD) is a neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the HTT gene for which no therapies are available. This mutation causes HTT protein misfolding and aggregation, preferentially affecting medium spiny neurons (MSNs) of the basal ganglia. Transcriptional perturbations in synaptic genes and neuroinflammation are key processes that precede MSN dysfunction and motor symptom onset. Understanding the interplay between these processes is crucial to develop effective therapeutic strategies to treat HD. We investigated whether protein kinase CK2, a kinase upregulated in MSNs in HD and previously associated with Parkinsons disease (PD), participates in the regulation of neuroinflammation and synaptic function during HD progression. MethodsWe used the heterozygous knock-in zQ175 HD mouse model and compared that to zQ175 mice lacking one allele of CK2. We performed neuropathological analyses using immunohistochemistry, cytokine proteome profiling, RNA-seq analyses in the striatum, electrophysiological recordings, and behavioral analyses. We also used the murine immortalized striatal cell lines STHdhQ7 and STHdhQ111 and studied the expression of various synaptic genes dysregulated by CK2. ResultsWe showed that CK2 haploinsufficiency in zQ175 mice ameliorated neuroinflammation, HTT aggregation, transcriptional alterations, excitatory synaptic transmission, and motor coordination deficits. RNA-seq analyses also revealed a connection between -syn, a protein associated with PD, and the transcriptional perturbations mediated by CK2 in HD. We also found increased -syn serine 129 phosphorylation (pS129--syn), a post-translational modification linked to -synucleinopathy, in the nuclei of MSNs in zQ175 mice and in patients with HD. Levels of pS129--syn were ameliorated in zQ175 lacking one allele of CK2. ConclusionsOur data demonstrated that CK2 contributes to transcriptional dysregulation of synaptic genes and neuroinflammation in zQ175 mice and its depletion improved several HD-like phenotypes in this mouse model. These effects were related to increased phosphorylation of S129--syn in the striatum of HD mice, suggesting that CK2 contributes to worsening HD by mediating synucleinopathy. Our study highlights a possible convergent mechanism of neurodegeneration between HD and PD and suggests targeting CK2 as a potential therapeutic strategy to ameliorate synaptic dysfunction in HD as well as other neurodegenerative diseases.

neuroscience↗

bioRxiv2019

Activity-dependent regulation of the proapoptotic BH3-only gene egl-1 in a living neuron pair in C. elegans

The BH3-only family of proteins is key for initiating apoptosis in a variety of contexts, and may also contribute to non-apoptotic cellular processes. Historically, the nematode Caenorhabditis elegans has provided a powerful system for studying and identifying conserved regulators of BH3-only proteins. In C. elegans, the BH3-only protein EGL-1 is expressed during development to cell-autonomously trigger most developmental cell deaths. Here we provide evidence that egl-1 is also transcribed after development in the sensory neuron pair URX without inducing apoptosis. We used genetic screening and epistasis analysis to determine that its transcription is regulated in URX by neuronal activity and/or in parallel by orthologs of Protein Kinase G and the Salt-Inducible Kinase family. Because several BH3-only family proteins are also expressed in the adult nervous system of mammals, we suggest that studying egl-1 expression in URX may shed light on mechanisms that regulate conserved family members in higher organisms.

genetics↗