Neurobiology of Disease最新文献

{"title":"Astrocytic NLRP3 cKO mitigates depression-like behaviors induced by mild TBI in mice.","authors":"Hui-Tao Miao, Jun Wang, Jing-Jing Shao, Rong-Xin Song, Wen-Guang Li, Jian-Kai Sun, Shi-Yan Jia, Dong-Xue Zhang, Xiao-Ming Li, Jian-Yong Zhao, Li-Min Zhang","doi":"10.1016/j.nbd.2024.106785","DOIUrl":"10.1016/j.nbd.2024.106785","url":null,"abstract":"<p><strong>Background: </strong>Reports indicate that depression is a common mental health issue following traumatic brain injury (TBI). Our prior research suggests that Nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3)-related neuroinflammation, modulated by glial cells such as astrocytes, is likely to play a crucial role in the progression of anxiety and cognitive dysfunction. However, there is limited understanding of the potential of astrocytic NLRP3 in treating depression under mild TBI condition. This study aimed to determine whether astrocytic NLRP3 knockout (KO) could mitigate depressive-like behaviors following mild TBI and explore potential variations in such behaviors between genders post-mild TBI.</p><p><strong>Methods: </strong>Mild TBI was induced in mice using Feeney's weight-drop method. Behavioral assessments included neurological severity scores (NSS), social interaction test (SI), tail suspension test (TST), and forced swimming test (FST). Pathological changes were evaluated through immunofluorescence and local field potential (LFP) recordings at various time points post-injury.</p><p><strong>Results: </strong>Our findings indicated that astrocyte-specific NLRP3 KO decreased cleaved caspase-1 colocalized with astrocytes, decreased pathogenic astrocytes and increased Postsynaptic density protein 95 (PSD95) intensity, and significantly alleviated mild TBI-induced depression-like behaviors. It also led to the upregulation of protective astrocytes and apoptosis-associated factors, including cleaved caspase-3 post-mild TBI. Additionally, astrocyte-specific NLRP3 deletion resulting in improved θ and γ power and θ-γ phase coupling in the social interaction test (SI). Notably, under mild TBI conditions, astrocyte-specific NLRP3 exhibited greater neuroprotective effects in female knockout mice compared to males.</p><p><strong>Conclusion: </strong>Astrocyte NLRP3 knockout demonstrated a protective mechanism in mice subjected to mild TBI, possibly attributed to the inhibition of pyroptosis through the NLRP3 signaling pathway in astrocytes.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"205 ","pages":"106785"},"PeriodicalIF":5.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142966101","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pleiotropic effects of mutant huntingtin on retinopathy in two mouse models of Huntington's disease.","authors":"Hui Xu, Anakha Ajayan, Ralf Langen, Jeannie Chen","doi":"10.1016/j.nbd.2024.106780","DOIUrl":"10.1016/j.nbd.2024.106780","url":null,"abstract":"<p><p>Huntington's disease (HD) is caused by the expansion of a CAG repeat, encoding a string of glutamines (polyQ) in the first exon of the huntingtin gene (HTTex1). This mutant huntingtin protein (mHTT) with extended polyQ forms aggregates in cortical and striatal neurons, causing cell damage and death. The retina is part of the central nervous system (CNS), and visual deficits and structural abnormalities in the retina of HD patients have been observed. Defects in retinal structure and function are also present in the R6/2 and R6/1 HD transgenic mouse models that contain a gene fragment to express mHTTex1. We investigated whether these defects extend to the zQ175KI mouse model which is thought to be more representative of the human condition because it was engineered to contain the extended CAG repeat within the endogenous HTT locus. We found qualitatively similar phenotypes between R6/1 and zQ175KI retinae that include the presence of mHTT aggregates in retinal neurons, cone loss, downregulation of rod signaling proteins and abnormally elongated photoreceptor connecting cilia. In addition, we present novel findings that mHTT disrupts cell polarity in the photoreceptor cell layer and the retinal pigment epithelium (RPE). Furthermore, we show that the RPE cells from R6/1 mice contain mHTT nuclear inclusions, adding to the list of non-neuronal cells with mHTT aggregates and pathology. Thus, the eye may serve as a useful system to track disease progression and to test therapeutic intervention strategies for HD.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"106780"},"PeriodicalIF":5.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142907436","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synaptic modulation of glutamate in striatum of the YAC128 mouse model of Huntington disease.","authors":"Judy Cheng, Ellen T Koch, Daniel Ramandi, James P Mackay, Timothy P O'Leary, William Rees-Jones, Lynn A Raymond","doi":"10.1016/j.nbd.2024.106774","DOIUrl":"10.1016/j.nbd.2024.106774","url":null,"abstract":"<p><strong>Background: </strong>Altered balance between striatal direct and indirect pathways contributes to early motor, cognitive and psychiatric symptoms in Huntington disease (HD). While degeneration of striatal D2-type dopamine receptor (D2)-expressing indirect pathway medium spiny neurons (iMSNs) occurs prior to that of D1-type dopamine receptor (D1)-expressing direct pathway neurons, altered corticostriatal synaptic function precedes degeneration. D2-mediated signaling on iMSNs reduces their excitability and promotes endocannabinoid (eCB) synthesis, suppressing glutamate release from cortical afferents. D2 receptors are also expressed on glutamatergic cortical terminals, cholinergic interneurons, and dopaminergic terminals from substantia nigra where they suppress release of glutamate, acetylcholine and dopamine, respectively, and these cell types may contribute to early striatal dysfunction in HD. Thus, we used corticostriatal brain slices and optogenetic probes to directly investigate neuromodulatory signaling in the transgenic YAC128 HD mouse model.</p><p><strong>Results: </strong>Low-dose D2 agonist quinpirole reduced cortically-evoked glutamate release in dorsal striatum of premanifest YAC128 slices but not WT, and blocking type 1 cannabinoid receptors mitigated this effect. YAC128 corticostriatal brain slices also showed increased evoked dopamine and reduced evoked eCB release compared to WT, while acetylcholine signaling patterns remained relatively intact.</p><p><strong>Conclusions: </strong>These findings suggest that YAC128 corticostriatal slices show increased D2 sensitivity that is eCB-dependent, and that dopamine and eCB release are altered at an early disease stage. We provide evidence for impaired neuromodulatory signaling in early HD, guiding therapeutic efforts prior to the onset of overt motor symptoms later on.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"106774"},"PeriodicalIF":5.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142882328","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elevation of ganglioside degradation pathway drives GM2 and GM3 within amyloid plaques in a transgenic mouse model of Alzheimer's disease.","authors":"Wenxuan Wang, Sarah J Myers, Nikita Ollen-Bittle, Shawn N Whitehead","doi":"10.1016/j.nbd.2025.106798","DOIUrl":"10.1016/j.nbd.2025.106798","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a progressive neurodegenerative disease that accounts for two-thirds of all dementia cases, and age is the strongest risk factor. In addition to the amyloid hypothesis, lipid dysregulation is now recognized as a core component of AD pathology. Gangliosides are a class of membrane lipids of the glycosphingolipid family and are enriched in the central nervous system (CNS). Ganglioside dysregulation has been implicated in various neurodegenerative diseases, including AD, but the spatial distribution of ganglioside dysregulation with respect to amyloid-beta (Aβ) deposition is not well understood. To address this gap, matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) was employed to investigate the age-dependent expression profiles of the A-series ganglioside species GD1a, GM1, GM2, and GM3 in the APP/PS1 transgenic mouse model of AD in which age-dependent amyloid-beta (Aβ) plaques develop. This study utilized a dual-resolution approach in combination with whole-brain imaging for comprehensive detection of ganglioside expression across neuroanatomical regions via high-resolution imaging of the cerebral cortex and hippocampus to investigate plaque-associated ganglioside alterations. The results revealed age-dependent changes in the complex gangliosides GM1 and GD1a across white and gray matter regions in both wildtype and APP/PS1 mice. Significantly greater levels of simple gangliosides GM2 and GM3 were observed in the cortex and dentate gyrus of the hippocampus in transgenic mice at 12 and 18 m than in age-matched controls. The accumulation of GM3 colocalized with Aβ plaques in aged APP/PS1 mice and correlated with Hexa gene expression, suggesting that ganglioside degradation is a mechanism for the accumulation of GM3. This work is the first to demonstrate that age-related ganglioside dysregulation is spatiotemporally associated with Aβ plaques using sophisticated MSI and reveals novel mechanistic insights into lipid regulation in AD.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"205 ","pages":"106798"},"PeriodicalIF":5.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142966034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modeling sacsin depletion in Danio Rerio offers new insight on retinal defects in ARSACS.","authors":"Valentina Naef, Devid Damiani, Rosario Licitra, Maria Marchese, Stefania Della Vecchia, Matteo Baggiani, Letizia Brogi, Daniele Galatolo, Silvia Landi, Filippo Maria Santorelli","doi":"10.1016/j.nbd.2025.106793","DOIUrl":"10.1016/j.nbd.2025.106793","url":null,"abstract":"<p><p>Biallelic mutations in the SACS gene, encoding sacsin, cause early-onset autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), a neurodegenerative disease also characterized by unique and poorly understood retinal abnormalities. While two murine models replicate the phenotypic and neuronal features observed in patients, no retinal phenotype has been described so far. In a zebrafish knock-out strain that faithfully mirrors the main aspects of ARSACS, we observed impaired visual function due to photoreceptor degeneration, likely caused by cell cycle defects in progenitor cells. RNA-seq analysis in embryos revealed dysfunction in proteins related to fat-soluble vitamins (e.g., TTPA, RDH5, VKORC) and suggested a key role of neuroinflammation in driving the retinal defects. Our findings indicate that studying retinal pathology in ARSACS could be crucial for understanding the impact of sacsin depletion and may offer insights into halting disease progression.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"106793"},"PeriodicalIF":5.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11757156/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142952067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Globular-shaped Aβ oligomers have diverse mechanisms for promoting Aβ aggregations with the facilitation of fibril elongation.","authors":"Hiroto Nakano, Sadao Hikishima, Makoto Mori, Jota Minamikawa, Daiki Muramatsu, Yasuhiro Sakashita, Tokuhei Ikeda, Moeko Noguchi-Shinohara, David B Teplow, Kenjiro Ono","doi":"10.1016/j.nbd.2024.106775","DOIUrl":"10.1016/j.nbd.2024.106775","url":null,"abstract":"<p><p>The accumulation of amyloid β-proteins (Aβ) in the extracellular space, forming insoluble plaques, is a primary pathological process underlying Alzheimer's disease (AD). Among the various Aβ species that appear during Aβ aggregation, Aβ oligomers are considered the most neurotoxic form. However, the precise mechanisms of their molecular functions within the Aβ aggregation cascade have not been clarified so far. This research aimed to uncover the structural and functional characteristics of globular-shaped Aβ oligomers (gAβO) under in vitro conditions. We performed thioflavin T (ThT) assays on low-molecular-weight (LMW) Aβ42, testing different concentrations of Aβ42 mature fibril (MF) seeds and gAβO. Fibril formation was continuously observed using high-speed atomic force microscopy (HS-AFM) in LMW Aβ42 with different sample conditions. Conformational changes of Aβ42 aggregates in the presence of gAβO was also evaluated using circular dichroism spectroscopy. The results of the ThT analysis and HS-AFM observation indicated that gAβO promoted fibril formation of LMW Aβ42 while gAβO itself did not form fibrous aggregates, indicating that gAβO would have a catalytic effects on LMW Aβ42 aggregation. We also showed that the molecular interaction of gAβO was altered by the presence and amount of MF seeds in the reaction buffers, indicating that complex interactions would exist among different Aβ species. The results of our present research demonstrated that gAβO would have significant roles to accelerate Aβ aggregation in AD pathogenesis. 225 < 250 words.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"106775"},"PeriodicalIF":5.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142886020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"iPSC models of mitochondrial diseases.","authors":"Sonja Heiduschka, Alessandro Prigione","doi":"10.1016/j.nbd.2025.106822","DOIUrl":"https://doi.org/10.1016/j.nbd.2025.106822","url":null,"abstract":"<p><p>Mitochondrial diseases are historically difficult to study. They cause multi-systemic defects with prevalent impairment of hard-to-access tissues such as the brain and the heart. Furthermore, they suffer from a paucity of conventional model systems, especially because of the challenges associated with mitochondrial DNA (mtDNA) engineering. Consequently, most mitochondrial diseases are currently untreatable. Human induced pluripotent stem cells (iPSCs) represent a promising approach for developing human model systems and assessing therapeutic avenues in a patient- and tissue-specific context. iPSCs are being increasingly used to investigate mitochondrial diseases, either for dissecting mutation-specific defects within two-dimensional (2D) or three-dimensional (3D) progenies or for unveiling the impact of potential treatment options. Here, we review how iPSC-derived 2D cells and 3D organoid models have been applied to the study of mitochondrial diseases caused by either nuclear or mtDNA defects. We anticipate that the field of iPSC-driven modeling of mitochondrial diseases will continue to grow, likely leading to the development of innovative platforms for treatment discovery and toxicity that could benefit the patient community suffering from these debilitating disorders with highly unmet medical needs.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"106822"},"PeriodicalIF":5.1,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143075138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aberrant functional connectome gradient and its neurotransmitter basis in Parkinson's disease.","authors":"Tao Guo, Cheng Zhou, Jiaqi Wen, Jingjing Wu, Yaping Yan, Jianmei Qin, Min Xuan, Haoting Wu, Chenqing Wu, Jingwen Chen, Sijia Tan, Xiaojie Duanmu, Baorong Zhang, Xiaojun Xu, Minming Zhang, Xiaojun Guan","doi":"10.1016/j.nbd.2025.106821","DOIUrl":"10.1016/j.nbd.2025.106821","url":null,"abstract":"<p><p>Patients with Parkinson's disease (PD) exhibit heterogenous clinical deficits not only in motor function, other deficits in both sensory and higher-order cognitive processing are also involved. Connectome studies have suggested a primary-to-transmodal gradient and a primary-to-primary gradient in functional brain networks, supporting the spectrum from sensation to cognition. However, whether these gradients are altered in PD patients and how these alterations associate with neurotransmitter profiles remain unknown. By constructing functional network and calculating its gradient in 134 PD patients and 172 normal controls, we compared functional connectivity gradients between groups and performed spearman correlation to explore the association between neurotransmitter expression and functional network gradient-based alternations in PD. Decreased first gradients were detected mainly in association cortex, including frontal cortex, insula, cingulate, and parietal cortex, corresponding to the decrement of frontoparietal/ventral attention network observed in network-level analyses. Decreased second gradients were observed in primary motor and somatosensory cortex, meeting the decrement of somatomotor network at the network level. Besides, network-level comparisons revealed the increment of visual network in the first gradient and increment of ventral attention network in the second gradient. Transcription-neuroimaging association analyses showed that changes of the first gradient were mainly negatively correlated with nondopaminergic system, while alterations of the second gradient were positively correlated with both dopaminergic and nondopaminergic systems. These results highlight the connectome gradient dysfunction in PD and its linkage with neurotransmitter expression profiles, providing insight into the molecular mechanisms for functional alterations underlying PD.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"106821"},"PeriodicalIF":5.1,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143075137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Current safety recommendations for handling mouse and human αsynuclein pre-formed fibrils.","authors":"Lauren Fielding, Marissa A Menard, Justin Roth, Maria Iuliano, Benjamin Dehay, Patricia Aguilar-Calvo, Laura A Volpicelli-Daley","doi":"10.1016/j.nbd.2025.106820","DOIUrl":"https://doi.org/10.1016/j.nbd.2025.106820","url":null,"abstract":"<p><p>α-Synuclein (α-syn) can form amyloid fibrils. Lewy bodies and Lewy neurites containing aggregated α-syn are pathological markers of Parkinson's Disease and Dementia with Lewy Bodies. To better understand the role of pathological α-syn in disease, many labs use α-syn preformed fibrils (PFFs). Neurons take up the PFFs, which act as seeds to corrupt endogenously expressed α-syn, inducing it to form aggregates very similar to those found in diseased brains. The PFFs are typically generated using recombinant mouse or human α-syn. α-Syn fibrils can also be extracted or amplified from brain tissue extracts, cerebrospinal fluid, or skin biopsies from patients with known synucleinopathy. The PFFs are then added to cell culture, or injected into rodents or primates to induce pathology. Because PFFs can corrupt endogenous α-syn, researchers should adhere to strict safety protocols when handling PFFs to minimize potential exposures. Our group consulted with biosafety professionals at the University of Alabama at Birmingham (UAB) to identify potential risks related to working with α-syn PFFs and offer containment controls to mitigate those risks. Potential exposures include pipetting, opening tubes, and sonication of the PFFs to generate fragments, all of which could potentially generate aerosols. Here, we outline best practices for the safe conduct of research with α-syn fibrils, including personal protective equipment and decontamination procedures. We highlight steps in which extra precautions should be taken and how to minimize exposure and potential risk associated with use of PFFs in scientific research.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"206 ","pages":"106820"},"PeriodicalIF":5.1,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143075139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Estrogen-related receptor gamma is a regulator of mitochondrial, autophagy, and immediate-early gene programs in spiny projection neurons: Relevance for transcriptional changes in Huntington disease.","authors":"Stephanie N Fox, Cody H Savage, Narcy R Amireddy, Laura J McMeekin, David K Crossman, Peter J Detloff, Michelle Gray, Rita M Cowell","doi":"10.1016/j.nbd.2025.106818","DOIUrl":"10.1016/j.nbd.2025.106818","url":null,"abstract":"<p><p>Mitochondrial dysfunction, transcriptional dysregulation, and protein aggregation are hallmarks of multiple neurodegenerative disorders, including Huntington's disease (HD). Strategies are needed to counteract these processes to restore neuronal health and function in HD. Recent evidence indicates that the transcription factor estrogen-related receptor gamma (ERRγ/Esrrg) is required for normal expression of mitochondrial, synaptic, and autophagy genes in neurons. Further, overexpression of Esrrg in dopaminergic neurons reduces synuclein load in the pre-formed fibril model of synucleinopathy. For these reasons, we sought to understand ERRγ's role in transcriptional regulation in spiny projection neurons (SPNs), one of the neuronal populations vulnerable to transcriptional dysregulation, mitochondrial dysfunction, and protein aggregation in HD. Here, we demonstrate that developmental deletion of Esrrg selectively in SPNs causes a transcriptional pattern consistent with a reduction of Drd1 and Drd2-positive neurons in the mouse dorsolateral striatum. To avoid effects of developmental deletion and explore Esrrg's role within adult SPN populations, we deleted or overexpressed Esrrg in adult SPNs. While overexpression was sufficient to increase the expression of mitochondrial and lysosome-related transcripts, Esrrg deletion surprisingly caused increased expression of immediate-early genes and genes with enrichment of binding sites for transcriptional repressors. In contrast, these genes were downregulated by Esrrg overexpression. Concordantly, Esrrg-deficient mice exhibited lack of amphetamine-induced hyperactivity and further upregulation of immediate-early genes. To determine whether the alterations observed with ERRγ modulation have any relevance for understanding transcriptional changes in SPNs in neurodegeneration, we measured Esrrg and its responsive genes in two mouse models of HD. We found an increase in Esrrg expression in HD models, accompanied by a transcriptional profile with similarities to that observed with Esrrg overexpression, suggesting the existence of an ERRγ-dependent, stress-related response. Altogether, these studies suggest that ERRγ is a key activator of mitochondrial and lysosomal transcripts in SPNs with a potential bi-functional role as a mediator of immediate-early gene repression. Ongoing studies are investigating mechanisms underlying ERRγ's roles in transcriptional activation and repression in SPNs to inform strategies to promote neuroprotective actions of ERRγ in SPNs in HD.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"106818"},"PeriodicalIF":5.1,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}