Bergh Sofia, Casadei Nicolas, Gabery Sanaz, Simonsson Oskar, Duarte João M N, Kirik Deniz, Nguyen Huu Phuc, Petersén Åsa
Translational Neuroendocrine Research Unit (TNU), Department of Experimental Medical Science, Lund University, BMC D11, Lund, 221 84, Sweden.
Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
Acta Neuropathol Commun. 2025 May 27;13(1):119. doi: 10.1186/s40478-025-02018-8.
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.
TAR DNA结合蛋白43（TDP - 43）病理学与神经退行性疾病肌萎缩侧索硬化症（ALS）、额颞叶痴呆（FTD）和亨廷顿舞蹈病（HD）相关。这些疾病都存在代谢和情绪调节异常，可能是由下丘脑病理学改变引起的。在临床ALS患者的下丘脑中存在TDP - 43包涵体，同时表达调节代谢和情绪的神经肽（如食欲素、促黑素细胞激素和催产素）的下丘脑神经元出现选择性丢失。我们旨在研究下丘脑TDP - 43的作用与神经病理学发展以及代谢和行为变化之间是否存在因果关系。我们构建了一种腺相关病毒（AAV）载体，该载体在神经元特异性突触素启动子的控制下表达人TDP - 43，并将其双侧注射到野生型FVB/N小鼠的下丘脑。TDP - 43的过表达导致下丘脑病理学改变，呈剂量依赖性，复制了临床病理学特征，包括下丘脑萎缩以及表达食欲素、促黑素细胞激素和催产素的神经元丢失。在下丘脑中发现了TDP - 43的核内和胞质包涵体。下丘脑过表达TDP - 43的小鼠出现代谢失调，伴有高血糖，且与食物摄入量无关。此外，下丘脑过表达TDP - 43的小鼠运动活性和筑巢能力降低，提示出现了类似冷漠的表型。综上所述，AAV载体介导的下丘脑TDP - 43过表达导致神经病理学改变，并伴有代谢功能障碍和类似冷漠行为的发展。这些结果表明，TDP - 43可在下丘脑中发挥直接的病理作用，这可能有助于TDP - 43蛋白病非运动表型的发展。
