TDP-43 overexpression in the hypothalamus drives neuropathology, dysregulates metabolism and impairs behavior in mice
Abstract TAR DNA-binding protein 43 (TDP-43) pathology is linked to the neurodegenerative disorders amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Huntington disease (HD). Dysregulation of metabolism and emotion is shared across these disorders and may be caused by hypothalam...
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BMC
2025-05-01
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| Series: | Acta Neuropathologica Communications |
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| Online Access: | https://doi.org/10.1186/s40478-025-02018-8 |
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| author | Sofia Bergh Nicolas Casadei Sanaz Gabery Oskar Simonsson João M. N. Duarte Deniz Kirik Huu Phuc Nguyen Åsa Petersén |
| author_facet | Sofia Bergh Nicolas Casadei Sanaz Gabery Oskar Simonsson João M. N. Duarte Deniz Kirik Huu Phuc Nguyen Åsa Petersén |
| author_sort | Sofia Bergh |
| collection | DOAJ |
| description | Abstract TAR DNA-binding protein 43 (TDP-43) pathology is linked to the neurodegenerative disorders amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Huntington disease (HD). Dysregulation of metabolism and emotion is shared across these disorders and may be caused by hypothalamic pathology. Inclusions with TDP-43 are present in the hypothalamus in clinical ALS, as well as selective loss of hypothalamic neurons expressing the metabolism and emotion regulating neuropeptides hypocretin (orexin), melanin-concentrating hormone (MCH) and oxytocin. We aimed to investigate whether there is a casual link between the effects of TDP-43 in the hypothalamus and the development of neuropathology, as well as changes in metabolism and behavior. We generated an adeno-associated viral (AAV) vector expressing human TDP-43 under the neuronal-specific synapsin promoter, which was injected bilaterally into the hypothalamus of wild-type FVB/N mice. TDP-43 overexpression resulted in hypothalamic pathology in a dose-dependent fashion replicating clinical pathology with hypothalamic atrophy and loss of hypocretin-, MCH- and oxytocin-expressing neurons. Nuclear and cytoplasmic inclusions of TDP-43 were found in the hypothalamus. Mice overexpressing TDP-43 in the hypothalamus developed metabolic dysregulation with hyperglycaemia independent of food intake. Additionally, mice overexpressing TDP-43 in the hypothalamus exhibited reduced motor activity and nesting ability, suggesting the development of an apathy-like phenotype. Taken together, AAV-vector mediated TDP-43 overexpression in the hypothalamus leads to neuropathology with the development of metabolic dysfunction and apathy-like behavior. These results indicate that TDP-43 can exert direct pathological effects in the hypothalamus, which may contribute to the development of the non-motor phenotype in TDP-43 proteinopathies. |
| format | Article |
| id | doaj-art-15c02dad965c4aefabe3818e4be24e6b |
| institution | OA Journals |
| issn | 2051-5960 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj-art-15c02dad965c4aefabe3818e4be24e6b2025-08-20T02:00:13ZengBMCActa Neuropathologica Communications2051-59602025-05-0113112110.1186/s40478-025-02018-8TDP-43 overexpression in the hypothalamus drives neuropathology, dysregulates metabolism and impairs behavior in miceSofia Bergh0Nicolas Casadei1Sanaz Gabery2Oskar Simonsson3João M. N. Duarte4Deniz Kirik5Huu Phuc Nguyen6Åsa Petersén7Translational Neuroendocrine Research Unit (TNU), Department of Experimental Medical Science, Lund UniversityInstitute of Medical Genetics and Applied Genomics, University of TübingenTranslational Neuroendocrine Research Unit (TNU), Department of Experimental Medical Science, Lund UniversityTranslational Neuroendocrine Research Unit (TNU), Department of Experimental Medical Science, Lund UniversityDiabetes and Brain Function Unit, Department of Experimental Medical Science, Lund UniversityBrain Repair and Imaging in Neural Systems (BRAINS), Department of Experimental Medical Science, Lund UniversityDepartment of Human Genetics, Medical Faculty, Ruhr University BochumTranslational Neuroendocrine Research Unit (TNU), Department of Experimental Medical Science, Lund UniversityAbstract TAR DNA-binding protein 43 (TDP-43) pathology is linked to the neurodegenerative disorders amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Huntington disease (HD). Dysregulation of metabolism and emotion is shared across these disorders and may be caused by hypothalamic pathology. Inclusions with TDP-43 are present in the hypothalamus in clinical ALS, as well as selective loss of hypothalamic neurons expressing the metabolism and emotion regulating neuropeptides hypocretin (orexin), melanin-concentrating hormone (MCH) and oxytocin. We aimed to investigate whether there is a casual link between the effects of TDP-43 in the hypothalamus and the development of neuropathology, as well as changes in metabolism and behavior. We generated an adeno-associated viral (AAV) vector expressing human TDP-43 under the neuronal-specific synapsin promoter, which was injected bilaterally into the hypothalamus of wild-type FVB/N mice. TDP-43 overexpression resulted in hypothalamic pathology in a dose-dependent fashion replicating clinical pathology with hypothalamic atrophy and loss of hypocretin-, MCH- and oxytocin-expressing neurons. Nuclear and cytoplasmic inclusions of TDP-43 were found in the hypothalamus. Mice overexpressing TDP-43 in the hypothalamus developed metabolic dysregulation with hyperglycaemia independent of food intake. Additionally, mice overexpressing TDP-43 in the hypothalamus exhibited reduced motor activity and nesting ability, suggesting the development of an apathy-like phenotype. Taken together, AAV-vector mediated TDP-43 overexpression in the hypothalamus leads to neuropathology with the development of metabolic dysfunction and apathy-like behavior. These results indicate that TDP-43 can exert direct pathological effects in the hypothalamus, which may contribute to the development of the non-motor phenotype in TDP-43 proteinopathies.https://doi.org/10.1186/s40478-025-02018-8(4 to 6): TDP-43HypothalamusMetabolismAmyotrophic lateral sclerosisFrontotemporal dementia |
| spellingShingle | Sofia Bergh Nicolas Casadei Sanaz Gabery Oskar Simonsson João M. N. Duarte Deniz Kirik Huu Phuc Nguyen Åsa Petersén TDP-43 overexpression in the hypothalamus drives neuropathology, dysregulates metabolism and impairs behavior in mice Acta Neuropathologica Communications (4 to 6): TDP-43 Hypothalamus Metabolism Amyotrophic lateral sclerosis Frontotemporal dementia |
| title | TDP-43 overexpression in the hypothalamus drives neuropathology, dysregulates metabolism and impairs behavior in mice |
| title_full | TDP-43 overexpression in the hypothalamus drives neuropathology, dysregulates metabolism and impairs behavior in mice |
| title_fullStr | TDP-43 overexpression in the hypothalamus drives neuropathology, dysregulates metabolism and impairs behavior in mice |
| title_full_unstemmed | TDP-43 overexpression in the hypothalamus drives neuropathology, dysregulates metabolism and impairs behavior in mice |
| title_short | TDP-43 overexpression in the hypothalamus drives neuropathology, dysregulates metabolism and impairs behavior in mice |
| title_sort | tdp 43 overexpression in the hypothalamus drives neuropathology dysregulates metabolism and impairs behavior in mice |
| topic | (4 to 6): TDP-43 Hypothalamus Metabolism Amyotrophic lateral sclerosis Frontotemporal dementia |
| url | https://doi.org/10.1186/s40478-025-02018-8 |
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