Loss of the thyroid hormone-binding protein Crym renders striatal neurons more vulnerable to mutant huntingtin in Huntington's disease

Francelle, Laetitia; Galvan, Laurie; Gaillard, Marie-Claude; Guillermier, Martine; Houitte, Diane; Bonvento, Gilles; Petit, Fanny; Jan, Caroline; Dufour, Noëlle; Hantraye, Philippe; Elalouf, Jean‐Marc; Chaldée, Michel de; Déglon, Nicole; Brouillet, Emmanuel

doi:10.1093/hmg/ddu571

Cited by 29 publications

(29 citation statements)

References 56 publications

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“…To our knowledge, the discovery that μ-crystallin is specific for striatal astrocytes provides the first molecular marker that defines a region-specific astrocyte population. Moreover, striatal astrocytes are known to be altered in Huntington’s disease (HD) (Khakh et al, 2017) and μ-crystallin levels decrease in humans and mouse models of HD (Francelle et al, 2015). Interestingly, six of the top 40 striatal enriched astrocyte genes are histones, which is consistent with the GSEA results that chromosome structure-related gene sets were striatal enriched.…”

Section: Discussionmentioning

confidence: 99%

Neural Circuit-Specialized Astrocytes: Transcriptomic, Proteomic, Morphological, and Functional Evidence

Chai

Díaz-Castro

Shigetomi

et al. 2017

Neuron

605

739

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Summary Astrocytes are ubiquitous in the brain and are widely held to be largely identical. However, this view has not been fully tested and the possibility that astrocytes are neural circuit-specialized remains largely unexplored. Here, we used multiple, integrated approaches including RNA-Seq, mass spectrometry, electrophysiology, immunohistochemistry, serial block-face scanning electron microscopy, morphological reconstructions, pharmacogenetics, as well as diffusible dye, calcium and glutamate imaging, to directly compare adult striatal and hippocampal astrocytes under identical conditions. We found significant differences between striatal and hippocampal astrocytes in electrophysiological properties, Ca2+ signaling, morphology and astrocyte-synapse proximity. Unbiased evaluation of actively translated RNA and proteomic data confirmed significant astrocyte diversity between hippocampal and striatal circuits. We thus report core astrocyte properties, reveal evidence for specialized astrocytes within neural circuits and provide new, integrated database resources and approaches to explore astrocyte diversity and function throughout the adult brain.

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Section: Discussionmentioning

confidence: 99%

Neural Circuit-Specialized Astrocytes: Transcriptomic, Proteomic, Morphological, and Functional Evidence

Chai

Díaz-Castro

Shigetomi

et al. 2017

Neuron

605

739

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“…We identified 2 key drivers that met all 5 criteria (Figure 5B-I): crystalin mu (Crym) and prostaglandin D2 synthase (Ptgds). Crym is a thyroid hormonebinding protein (Hallen et al, 2011;Vie et al, 1997), a non-canonical transcriptional regulator (Ohkubo et al, 2019), and is neuroprotective in striatum (Francelle et al, 2015), while Ptgds is a pro-inflammatory enzyme which catalyzes the production of prostaglandin D (Urade and Hayaishi, 2011). Since we hypothesized that transcriptional changes within meA drive sex-specific changes in behavior, we chose to focus on Crym ( Figure 5J-M).…”

Section: Co-expression Analysis Reveals That Feminization and Masculimentioning

confidence: 99%

Adolescent Social Isolation Reprograms the Medial Amygdala: Transcriptome and Sex Differences in Reward

Walker

Zhou

Ramakrishnan

et al. 2020

Preprint

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Adolescence is a sensitive window for reward-and stress-associated behavior. Although stress during this period causes long-term changes in behavior in males, how females respond is relatively unknown. Here we show that social isolation stress in adolescence, but not adulthood, induces persistent but opposite effects on anxiety-and cocaine-related behaviors in male vs. female mice, and that these effects are reflected in transcriptional profiles within the adult medial amygdala (meA). By integrating differential gene expression with co-expression network analyses, we identified crystallin mu (Crym), a thyroid-binding protein, as a key driver of these transcriptional profiles. Manipulation of Crym specifically within adult meA neurons recapitulates the behavioral and transcriptional effects of social isolation and re-opens a window of plasticity that is otherwise closed. Our results establish that meA is essential for sex-specific responses to stressful and rewarding stimuli through transcriptional programming that occurs during adolescence. INTRODUCTION:In many mammals, sex differences in behavior are required for the perpetuation of the species and are expressed as differences in mating and reproductive strategies. Individual variations in reproductive strategies are known to be dependent on e n v i r o n m e n t a l f a c t o r s a n d r e l y o n programming mediated by experiencedependent plasticity (Bergan et al., 2014). Stressful and rewarding stimuli are two key factors that may be especially important for encoding these strategies to optimize sexual behaviors and maximize reproductive success . However, very little is known about the brain region-specific m o l e c u l a r p r o c e s s e s u n d e r l y i n g t h e programming of such strategies.Adolescence is a sensitive period for programming reward-associated behaviors particularly in males (Sisk, 2016;Walker et al., 2019) and a time of heightened responsiveness to rewarding and stressful Statistical Analysis of Behavioral DataAll behaviors were analyzed using a 2-way ANOVA or a Kruskall-Wallis non-parametric test depending on the significance of a Levene's test for homogeneity of variance. If an interaction was identified, a Tukey post-hoc analysis was conducted to determine specific differences between groups. If an effect was identified via Kruskall-Wallis, follow-up Mann-Whitney tests were run to determine specific differences between groups. Chi-square tests were used to determine differences in the distribution of behavioral phenotypes within a group (marble burying and CPP). Pearson's Chi Squared tests were used to account for the lack of representation of all categories across groups. All analyses were conducted using SPSS Statistical Software, V25 (IBM, Armonk, NY). Cocaine Injections and Tissue Collection for RNA-seqOn P80, animals were divided into 8 groups of males and 8 groups of females: GH + chronic cocaine/saline; SI + chronic cocaine /saline; GH + acute cocaine/saline; SI + acute cocaine/saline. In total, 200 animals were utlilized. F...

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“…Previous studies have reported downregulation of CRYM mRNA in Huntington's disease models and patients and CRYM plays a neuroprotective role in the striatum of Huntington's disease model mice . Huntington's disease is a neurodegenerative disease characterized by loss of neurons in the caudate nucleus resulting in involuntary movements and cognitive impairment.…”

Section: Discussionmentioning

confidence: 99%

Expression of CRYM in different rat organs during development and its decreased expression in degenerating pyramidal tracts in amyotrophic lateral sclerosis

et al. 2018

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The protein μ-crystallin (CRYM) is a novel component of the marsupial lens that has two functions: it is a key regulator of thyroid hormone transportation and a reductase of sulfur-containing cyclic ketimines. In this study, we examined changes of the expression pattern of CRYM in different rat organs during development using immunohistochemistry and immunoblotting. As CRYM is reportedly expressed in the corticospinal tract, we also investigated CRYM expression in human cases of amyotrophic lateral sclerosis (ALS) using immunohistochemistry. In the rat brain, CRYM was expressed in the cerebral cortex, basal ganglia, hippocampus and corticospinal tract in the early postnatal period. As postnatal development progressed, CRYM expression was restricted to large pyramidal neurons in layers V and VI of the cerebral cortex and pyramidal cells in the deep layer of CA1 in the hippocampus. Even within the same regions, CRYM-positive and negative neurons were distributed in a mosaic pattern. In the kidney, CRYM was expressed in epithelial cells of the proximal tubule and mesenchymal cells of the medulla in the early postnatal period; however, CRYM expression in the medulla was lost as mesenchymal cell numbers decreased with the rapid growth of the medulla. In human ALS brains, we observed marked loss of CRYM in the corticospinal tract, especially distally. Our results suggest that CRYM may play roles in development of cortical and hippocampal pyramidal cells in the early postnatal period, and in the later period, performs cell-specific functions in selected neuronal populations. In the kidney, CRYM may play roles in maturation of renal function. The expression patterns of CRYM may reflect significance of its interactions with T3 or ketimines in these cells and organs. The results also indicate that CRYM may be used as a marker of axonal degeneration in the corticospinal tract.

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Loss of the thyroid hormone-binding protein Crym renders striatal neurons more vulnerable to mutant huntingtin in Huntington's disease

Cited by 29 publications

References 56 publications

Neural Circuit-Specialized Astrocytes: Transcriptomic, Proteomic, Morphological, and Functional Evidence

Neural Circuit-Specialized Astrocytes: Transcriptomic, Proteomic, Morphological, and Functional Evidence

Adolescent Social Isolation Reprograms the Medial Amygdala: Transcriptome and Sex Differences in Reward

Expression of CRYM in different rat organs during development and its decreased expression in degenerating pyramidal tracts in amyotrophic lateral sclerosis

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