| 1. |
- Dickson, Elna, et al.
(författare)
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Altered Adipocyte Cell Size Distribution Prior to Weight Loss in the R6/2 Model of Huntington's Disease
- 2023
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Ingår i: Journal of Huntington's disease. - 1879-6397. ; 12:3, s. 253-266
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Metabolic alterations contribute to disease onset and prognosis of Huntington's disease (HD). Weight loss in the R6/2 mouse model of HD is a consistent feature, with onset in mid-to-late stage of disease.OBJECTIVE: In the present study, we aimed to investigate molecular and functional changes in white adipose tissue (WAT) that occur at weight loss in R6/2 mice. We further elaborated on the effect of leptin-deficiency and early obesity in R6/2 mice.METHODS: We performed analyses at 12 weeks of age; a time point that coincides with the start of weight loss in our R6/2 mouse colony. Gonadal (visceral) and inguinal (subcutaneous) WAT depot weights were monitored, as well as adipocyte size distribution. Response to isoprenaline-stimulated glycerol release and insulin-stimulated glucose uptake in adipocytes from gonadal WAT was assessed.RESULTS: In R6/2 mice, WAT depot weights were comparable to wildtype (WT) mice, and the response to insulin and isoprenaline in gonadal adipocytes was unaltered. Leptin-deficient R6/2 mice exhibited distinct changes compared to leptin-deficient WT mice. At 12 weeks, female leptin-deficient R6/2 mice had reduced body weight accompanied by an increased proportion of smaller adipocytes, while in contrast; male mice displayed a shift towards larger adipocyte sizes without a significant body weight reduction at this timepoint.CONCLUSIONS: We here show that there are early sex-specific changes in adipocyte cell size distribution in WAT of R6/2 mice and leptin-deficient R6/2 mice.
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| 2. |
- Dickson, Elna, et al.
(författare)
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Hypothalamic expression of huntingtin causes distinct metabolic changes in Huntington's disease mice
- 2022
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Ingår i: Molecular Metabolism. - : Elsevier BV. - 2212-8778. ; 57
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: In Huntington's disease (HD), the disease-causing huntingtin (HTT) protein is ubiquitously expressed and causes both central and peripheral pathology. In clinical HD, a higher body mass index has been associated with slower disease progression, indicating that metabolic changes may be involved in disease pathogenesis. Underlying mechanisms of metabolic changes in HD are not fully known, but recent studies suggest involvement of hypothalamic dysfunction. The aim of the present study was to investigate whether modulation of hypothalamic HTT levels would affect metabolic phenotype and disease features in HD using mouse models.METHODS: We used the R6/2 and BACHD mouse models that express different lengths of mutant HTT and respectively develop lean- and obese phenotypes. We utilized adeno-associated viral vectors to overexpress either mutant or wild-type HTT in the hypothalamus of R6/2, BACHD, and their wild-type littermates. Metabolic phenotype was assessed by body weight measurements over time and body composition analysis using dual-energy x-ray absorptiometry at the endpoint. R6/2 mice were further characterized using behavioral analyses, including rotarod, nesting- and hindlimb clasping tests during early- and late timepoints of disease progression. Finally, gene expression analysis was performed in R6/2 mice and wild-type littermates in order to assess transcriptional changes in hypothalamus and adipose tissue.RESULTS: Hypothalamic overexpression of mutant HTT induced significant gender-affected body weight gain in all models, including wild-type mice. In R6/2 females, early weight gain shifted to weight loss during the corresponding late stage of disease despite increased fat accumulation. Body weight changes were accompanied by behavioral alterations. During the period of early weight gain, R6/2 mice displayed a comparable locomotor capacity to wild-type mice. When assessing behavior just prior to weight loss onset in R6/2 mice, decreased locomotor performance was observed in R6/2 females with hypothalamic overexpression of mutant HTT. Transcriptional downregulation of beta-3 adrenergic receptor (B3AR), adipose triglyceride lipase (ATGL) and peroxisome proliferator-activated receptor gamma (PPARγ) in gonadal white adipose tissue was accompanied with distinct alterations in hypothalamic gene expression profiles in R6/2 females after mutant HTT overexpression. No significant effect on metabolic phenotype in R6/2 was seen in response to wild-type HTT overexpression.CONCLUSIONS: Taken together, our findings provide further support for a role of HTT in metabolic control via hypothalamic neurocircuits. Understanding the specific central neurocircuits and their peripheral link underlying metabolic imbalance in HD may open up avenues for novel therapeutic interventions.
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| 3. |
- Dickson, Elna, et al.
(författare)
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Microarray profiling of hypothalamic gene expression changes in Huntington’s disease mouse models
- 2022
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Structural changes and neuropathology in the hypothalamus have been suggested to contribute to the non-motor manifestations of Huntington’s disease (HD), a neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin (HTT) gene. In the present study, we investigated whether transcriptional changes would be part of hypothalamic pathology induced by the disease-causing huntingtin (HTT) protein. We performed microarray analysis using the Affymetrix platform on total hypothalamic RNA isolated from two HD mouse models and their littermate controls; BACHD mice with ubiquitous expression of full-length mutant HTT (mHTT) and wild-type mice with targeted hypothalamic overexpression of either wild-type HTT (wtHTT) or mHTT fragments. To analyze microarray datasets (34760 variables) and obtain functional implications of differential expression patterns, we used Linear Models for Microarray Data (limma) followed by Gene Set Enrichment Analysis (GSEA) using ClusterProfiler. Limma identified 735 and 721 significantly differentially expressed genes (adjusted p < 0.05) in hypothalamus of AAV datasets wtHTT vs control and mHTT vs control. In contrast, for BACHD datasets and the AAV mHTT vs. wtHTT dataset, none of the genes were differentially expressed (adjusted p-value > 0.05 for all probe IDs). In AAV groups, from the combined limma with GSEA using ClusterProfiler, we found both shared and unique gene sets and pathways for mice with wtHTT overexpression compared to mice with mHTT overexpression. mHTT caused widespread suppression of neuroendocrine networks, as evident by GSEA enrichment of GO-terms related to neurons and/or specific neuroendocrine populations. Using qRT-PCR, we confirmed that mHTT overexpression caused significant downregulation of key enzymes involved in neuropeptide synthesis, including histidine and dopa decarboxylases, compared to wtHTT overexpression. Multiple biosynthetic pathways such as sterol synthesis were among the top shared processes, where both unique and shared genes constituted leading-edge subsets. In conclusion, mice with targeted overexpression of HTT (wtHTT or mHTT) in the hypothalamus show dysregulation of pathways, of which there are subsets of shared pathways and pathways unique to either wtHTT or mHTT overexpression.
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| 4. |
- Dickson, Elna, et al.
(författare)
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Microarray profiling of hypothalamic gene expression changes in Huntington's disease mouse models
- 2022
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Ingår i: Frontiers in Neuroscience. - : Frontiers Media SA. - 1662-4548 .- 1662-453X. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- Structural changes and neuropathology in the hypothalamus have been suggested to contribute to the non-motor manifestations of Huntington's disease (HD), a neurodegenerative disorder caused by an expanded cytosine-adenine-guanine (CAG) repeat in the huntingtin (HTT) gene. In this study, we investigated whether hypothalamic HTT expression causes transcriptional changes. Hypothalamic RNA was isolated from two different HD mouse models and their littermate controls; BACHD mice with ubiquitous expression of full-length mutant HTT (mHTT) and wild-type mice with targeted hypothalamic overexpression of either wild-type HTT (wtHTT) or mHTT fragments. The mHTT and wtHTT groups showed the highest number of differentially expressed genes compared to the BACHD mouse model. Gene Set Enrichment Analysis (GSEA) with leading-edge analysis showed that suppressed sterol- and cholesterol metabolism were shared between hypothalamic wtHTT and mHTT overexpression. Most distinctive for mHTT overexpression was the suppression of neuroendocrine networks, in which qRT-PCR validation confirmed significant downregulation of neuropeptides with roles in feeding behavior; hypocretin neuropeptide precursor (Hcrt), tachykinin receptor 3 (Tacr3), cocaine and amphetamine-regulated transcript (Cart) and catecholamine-related biological processes; dopa decarboxylase (Ddc), histidine decarboxylase (Hdc), tyrosine hydroxylase (Th), and vasoactive intestinal peptide (Vip). In BACHD mice, few hypothalamic genes were differentially expressed compared to age-matched WT controls. However, GSEA indicated an enrichment of inflammatory- and gonadotropin-related processes at 10 months. In conclusion, we show that both wtHTT and mHTT overexpression change hypothalamic transcriptome profile, specifically mHTT, altering neuroendocrine circuits. In contrast, the ubiquitous expression of full-length mHTT in the BACHD hypothalamus moderately affects the transcriptomic profile.
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| 5. |
- Elabi, Osama, et al.
(författare)
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Human α-synuclein overexpression in a mouse model of Parkinson’s disease leads to vascular pathology, blood brain barrier leakage and pericyte activation
- 2021
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- The pathological hallmark of Parkinson’s disease (PD) is the formation of Lewy bodies containing aggregated alpha-synuclein (α-syn). Although PD is associated with these distinct histological changes, other pathological features such as microvascular alterations have been linked to neurodegeneration. These changes need to be investigated as they create a hostile brain microenvironment and may contribute to the development and progression of the disease. We use a human α-syn overexpression mouse model that recapitulates some of the pathological features of PD in terms of progressive aggregation of human α-syn, impaired striatal dopamine fiber density, and an age-dependent motor deficit consistent with an impaired dopamine release. We demonstrate for the first time in this model a compromised blood–brain barrier integrity and dynamic changes in vessel morphology from angiogenesis at earlier stages to vascular regression at later stages. The vascular alterations are accompanied by a pathological activation of pericytes already at an early stage without changing overall pericyte density. Our data support and further extend the occurrence of vascular pathology as an important pathophysiological aspect in PD. The model used provides a powerful tool to investigate disease-modifying factors in PD in a temporal sequence that might guide the development of new treatments.
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| 6. |
- Henningsen, Jo B, et al.
(författare)
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Effects of excitotoxicity in the hypothalamus in transgenic mouse models of Huntington disease
- 2021
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Ingår i: Heliyon. - : Elsevier BV. - 2405-8440. ; 7:8, s. 1-9
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Tidskriftsartikel (refereegranskat)abstract
- Huntington disease (HD) is a fatal neurodegenerative movement disorder caused by an expanded CAG repeat in the huntingtin gene (HTT). The mutant huntingtin protein is ubiquitously expressed, but only certain brain regions are affected. The hypothalamus has emerged as an important area of pathology with selective loss of neurons expressing the neuropeptides orexin (hypocretin), oxytocin and vasopressin in human postmortem HD tissue. Hypothalamic changes in HD may have implications for early disease manifestations affecting the regulation of sleep, emotions and metabolism. The underlying mechanisms of selective vulnerability of certain neurons in HD are not fully understood, but excitotoxicity has been proposed to play a role. Further understanding of mechanisms rendering neurons sensitive to mutant huntingtin may reveal novel targets for therapeutic interventions. In the present study, we wanted to examine whether transgenic HD mice display altered sensitivity to excitotoxicity in the hypothalamus. We first assessed effects of hypothalamic injections of the excitotoxin quinolinic acid (QA) into wild-type (WT) mice. We show that neuronal populations expressing melanin-concentrating hormone (MCH) and cocaine and amphetamine-regulated transcript (CART) display a dose-dependent sensitivity to QA. In contrast, neuronal populations expressing orexin, oxytocin, vasopressin as well as tyrosine hydroxylase in the A13 area are resistant to QA-induced toxicity. We demonstrate that the R6/2 transgenic mouse model expressing a short fragment of mutant HTT displays hypothalamic neuropathology with discrete loss of the neuronal populations expressing orexin, MCH, CART, and orexin at 12 weeks of age. The BACHD mouse model expressing full-length mutant HTT does not display any hypothalamic neuropathology at 2 months of age. There was no effect of hypothalamic injections of QA on the neuronal populations expressing orexin, MCH, CART or oxytocin in neither HD mouse model. In conclusion, we find no support for a role of excitotoxicity in the loss of hypothalamic neuronal populations in HD.
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| 7. |
- Hoque, Sanzana, et al.
(författare)
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Skeletal muscle regeneration is altered in the R6/2 mouse model of Huntington’s disease
- 2022
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Huntington’s disease (HD) is caused by CAG repeat expansion in the huntingtin (HTT) gene. Skeletal muscle wasting alongside central pathology is a well-recognized phenomenon seen in patients with HD and HD mouse models. HD muscle atrophy progresses with disease and affects prognosis and quality of life. Satellite cells, progenitors of mature skeletal muscle fibers, are essential for proliferation, differentiation, and repair of muscle tissue in response to muscle injury or exercise.In this study, we aim to investigate the effect of mutant HTT on the differentiation and regeneration capacity of HD muscle by employing in vitro mononuclear skeletal muscle cell isolation and in vivo acute muscle damage model in R6/2 mice.We found that, similar to R6/2 adult mice, neonatal R6/2 mice also exhibit a significant reduction in myofiber width and morphological changes in gastrocnemius and soleus muscles compared to WT mice. Cardiotoxin (CTX)-induced acute muscle damage in R6/2 and WT mice showed that the Pax7+ satellite cell pool was dampened in R6/2 mice at 4 weeks post-injection, and R6/2 mice exhibited an altered inflammatory profile in response to acute damage.Our results suggest that, in addition to the mutant HTT degenerative effects in mature muscle fibers, expression of mutant HTT in satellite cells might alter developmental and regenerative processes to contribute to the progressive muscle mass loss in HD. Taken together, the results presented here encourage further studies evaluating the underlying mechanisms of satellite cell dysfunction in HD mouse models.
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| 8. |
- Soylu-Kucharz, Rana, et al.
(författare)
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IKKβ signaling mediates metabolic changes in the hypothalamus of a Huntington disease mouse model
- 2022
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Ingår i: iScience. - : Elsevier BV. - 2589-0042. ; 25:2, s. 1-16
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Tidskriftsartikel (refereegranskat)abstract
- Huntington disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin (HTT) gene. Metabolic changes are associated with HD progression, but underlying mechanisms are not fully known. As the IKKβ/NF-κB pathway is an essential regulator of metabolism, we investigated the involvement of IKKβ, the upstream activator of NF-κB in hypothalamus-specific HD metabolic changes. We expressed amyloidogenic N-terminal fragments of mutant HTT (mHTT) in the hypothalamus of mice with brain-specific ablation of IKKβ (Nestin/IKKβlox/lox) and control mice (IKKβlox/lox). We assessed effects on body weight, metabolic hormones, and hypothalamic neuropathology. Hypothalamic expression of mHTT led to an obese phenotype only in female mice. CNS-specific inactivation of IKKβ prohibited weight gain in females, which was independent of neuroprotection and microglial activation. Our study suggests that mHTT in the hypothalamus causes metabolic imbalance in a sex-specific fashion, and central inhibition of the IKKβ pathway attenuates the obese phenotype.
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| 9. |
- Soylu Kucharz, Rana, et al.
(författare)
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Mutant huntingtin expression in the hypothalamus promotes ventral striatal neuropathology
- 2023
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Huntington’s disease is a fatal neurodegenerative disorder caused by an expanded CAG triplet repeat in the huntingtin (HTT) gene. Previous research focused on neuropathology in the striatum and its association with a typical movement disorder. Direct effects of mutant HTT (mHTT) in the striatum may cause neuropathology, although non-cell autonomous effects have also been suggested. Important non-motor features of HD include psychiatric symptoms and metabolic dysfunction, which may be linked to hypothalamic neuropathology. As hypothalamic neurons project to the ventral striatum, we hypothesized that expression of mHTT in the hypothalamus leads to disrupted neurotransmission in the ventral striatum and causes pathology. The overall aim of this study was to investigate the impact of mHTT expression in the hypothalamus on ventral striatal neuropathology and its contribution to non-HD motor symptoms. We demonstrate that selective expression of mHTT in the hypothalamus leads to the loss of dopamine and cAMP-regulated phosphoprotein (DARPP-32) immunopositive neurons in the ventral striatum in mice. Contrary to the effects of direct expression of mHTT in the hypothalamus, selective overexpression of mHTT in the ventral striatum does not affect body weight. Selective expression of mHTT in the ventral striatum leads to mHTT inclusion formation and loss of DARPP-32 neurons without affecting motor activity or anxiety-like behavior. We show that DARPP-32 neuron loss in the ventral striatum is recapitulated in the R6/2 mouse model of HD. Chemogenetic activation of hypothalamic neurons projecting to the ventral striatum had a blunted response in the R6/2 mice compared to wild-type mice, indicating a disrupted hypothalamus-ventral striatal circuitry. In summary, the expression of mHTT in the hypothalamus may impact the development of ventral striatal pathology in mice. This opens the possibility that non-cell-autonomous effects in the reward circuitry play a role in HD.
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| 10. |
- Stan, Tiberiu Loredan, et al.
(författare)
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Increased intestinal permeability and gut dysbiosis in the R6/2 mouse model of Huntington’s disease
- 2020
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Huntington’s disease (HD) is a progressive, multifaceted neurodegenerative disease associated with weight loss and gut problems. Under healthy conditions, tight junction (TJ) proteins maintain the intestinal barrier integrity preventing bacterial translocation from the intestinal lumen to the systemic circulation. Reduction of TJs expression in Parkinson’s disease patients has been linked with increased intestinal permeability—leaky gut syndrome. The intestine contains microbiota, most dominant phyla being Bacteroidetes and Firmicutes; in pathogenic or disease conditions the balance between these bacteria might be disrupted. The present study investigated whether there is evidence for an increased intestinal permeability and dysbiosis in the R6/2 mouse model of HD. Our data demonstrate that decreased body weight and body length in R6/2 mice is accompanied by a significant decrease in colon length and increased gut permeability compared to wild type littermates, without any significant changes in the protein levels of the tight junction proteins (occludin, zonula occludens). Moreover, we found an altered gut microbiota in R6/2 mice with increased relative abundance of Bacteroidetes and decreased of Firmicutes. Our results indicate an increased intestinal permeability and dysbiosis in R6/2 mice and further studies investigating the clinical relevance of these findings are warranted.
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