The hypothalamic lateral tuberal nucleus and the characteristics of neuronal loss in Huntington's disease

Kremer, H.P.H.; Roos, Raymund A.C.; Dingjan, Gemma M.; Bots, G. Th. A. M.; Bruyn, G.W.; Hofman, Michel A.

doi:10.1016/0304-3940(91)90443-w

Cited by 98 publications

(55 citation statements)

References 18 publications

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“…In patient suffering from Huntington's disease, the LTN incurs a substantial loss of cells (Kremer et al, 1991). In individuals with either Parkinson's or Alzheimer's disease, the number of cells does not change, but their characteristics do: they undergo cytoskeletal alterations and manifest cytoplasmatic inclusions such as Levy bodies (Hofman, 1997;Braak and Braak, 1998;Kremer, 1992;Kremer et al, 1990;Kremer and Bots, 1993).…”

Section: Discussionmentioning

confidence: 99%

The human lateral tuberal nucleus: Immunohistochemical characterization and analogy to the rodent PV1-nucleus

Gerig

Celio

2007

Brain Research

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A B S T R A C TThe lateral tuberal nucleus (LTN) is a hypothalamic region that has been identified with certainty only in humans and primates. It is composed of three small round globular units which protrude the basal surface of the brain along the optic tract. The function of the LTN is unknown. Recently, a tiny, parvalbumin-positive (PV1) nucleus was detected in the lateral hypothalamus of rodents. Like the human LTN, the rodent PV1-nucleus is subdivided into three units and lies along the optic tract. To ascertain whether the human LTN and the rodent PV1-nucleus could be considered as homologous structures not only based on their topographic location but also because of their neurochemical characteristics, we subjected tissue samples from humans, rats and mice to immunohistochemical analysis for a panel of neural markers. The human LTN was intensely immunoreactive for somatostatin and FF1, but only weakly so or not at all for parvalbumin, calbindin and calretinin. The rodent PV1-nucleus was intensely immunoreactive for parvalbumin but was not immunoreactive for either somatostatin, a surrogate for human FF1, calbindin or calretinin. Hence, using these neural markers, it was not possible to demonstrate a neurochemical homology between the human LTN and the rodent PV1-nucleus.

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Section: Discussionmentioning

confidence: 99%

The human lateral tuberal nucleus: Immunohistochemical characterization and analogy to the rodent PV1-nucleus

Gerig

Celio

2007

Brain Research

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“…In addition, atrophy and cell loss have also been described in the hypothalamus and hippocampus (Kremer et al, 1991;Spargo et al, 1993;Kassubek et al, 2004;Petersen et al, 2005). We evaluated the neuropathology in BACHD brains at 6 and 12 months of age.…”

Section: Progressive and Selective Neuropathology In Bachd Micementioning

confidence: 99%

Full-Length Human Mutant Huntingtin with a Stable Polyglutamine Repeat Can Elicit Progressive and Selective Neuropathogenesis in BACHD Mice

Gray¹,

Shirasaki²,

Cepeda³

et al. 2008

Journal of Neuroscience

570

696

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To elucidate the pathogenic mechanisms in Huntington's disease (HD) elicited by expression of full-length human mutant huntingtin (fl-mhtt), a bacterial artificial chromosome (BAC)-mediated transgenic mouse model (BACHD) was developed expressing fl-mhtt with 97 glutamine repeats under the control of endogenous htt regulatory machinery on the BAC. BACHD mice exhibit progressive motor deficits, neuronal synaptic dysfunction, and late-onset selective neuropathology, which includes significant cortical and striatal atrophy and striatal dark neuron degeneration. Power analyses reveal the robustness of the behavioral and neuropathological phenotypes, suggesting BACHD as a suitable fl-mhtt mouse model for preclinical studies. Additional analyses of BACHD mice provide novel insights into how mhtt may elicit neuropathogenesis. First, unlike previous fl-mhtt mouse models, BACHD mice reveal that the slowly progressive and selective pathogenic process in HD mouse brains can occur without early and diffuse nuclear accumulation of aggregated mhtt (i.e., as detected by immunostaining with the EM48 antibody). Instead, a relatively steady-state level of predominantly full-length mhtt and a small amount of mhtt N-terminal fragments are sufficient to elicit the disease process. Second, the polyglutamine repeat within fl-mhtt in BACHD mice is encoded by a mixed CAA-CAG repeat, which is stable in both the germline and somatic tissues including the cortex and striatum at the onset of neuropathology. Therefore, our results suggest that somatic repeat instability does not play a necessary role in selective neuropathogenesis in BACHD mice. In summary, the BACHD model constitutes a novel and robust in vivo paradigm for the investigation of HD pathogenesis and treatment.

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“…4 A few studies have also described that the hypothalamus is afflicted with clear neuronal loss occurring in the lateral tuberal nucleus. 5,6 Aside from causing cell death, misfolded huntingtin also accumulates in the cytoplasm and nucleus leading to the formation of aggregates. These inclusions also contain several other proteins including components of the ubiquitin-proteasome pathway, chaperones, synaptic proteins, and transcription factors.…”

Section: What Is Huntingtons Disease?mentioning

confidence: 99%

The use of the R6 transgenic mouse models of Huntington’s disease in attempts to develop novel therapeutic strategies

2005

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Summary:Huntington's disease (HD) is a genetic neurodegenerative disorder. Since identification of the disease-causing gene in 1993, a number of genetically modified animal models of HD have been generated. The first transgenic mouse models, R6/1 and R6/2 lines, were established 8 years ago. The R6/2 mice have been the best characterized and the most widely used model to study pathogenesis of HD and therapeutic interventions. In the present review, we especially focus on the characteristics of R6 transgenic mouse models and, in greater detail, describe the different therapeutic strategies that have been tested in these mice. We also, at the end, critically assess the relevance of the HD mouse models compared with the human disease and discuss how they can be best used in the future.

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The hypothalamic lateral tuberal nucleus and the characteristics of neuronal loss in Huntington's disease

Cited by 98 publications

References 18 publications

The human lateral tuberal nucleus: Immunohistochemical characterization and analogy to the rodent PV1-nucleus

The human lateral tuberal nucleus: Immunohistochemical characterization and analogy to the rodent PV1-nucleus

Full-Length Human Mutant Huntingtin with a Stable Polyglutamine Repeat Can Elicit Progressive and Selective Neuropathogenesis in BACHD Mice

The use of the R6 transgenic mouse models of Huntington’s disease in attempts to develop novel therapeutic strategies

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