Mechanisms of neurodegeneration in Huntington’s disease

Gil, Joana; Rego, A. Cristina

doi:10.1111/j.1460-9568.2008.06310.x

Cited by 405 publications

(308 citation statements)

References 275 publications

(549 reference statements)

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“…The biological functions of HD are not fully understood but both loss-of-function and gainof-function following mutant huntingtin expression have been described [3]. Alterations in mitochondria and in other organelles with increased oxidative stress are linked to disease progress in HD [5,6].…”

Section: Introductionmentioning

confidence: 99%

Downregulation of NF-κB signaling by mutant huntingtin proteins induces oxidative stress and cell death

Reijonen

Kukkonen

Hyrskyluoto

et al. 2010

Cell. Mol. Life Sci.

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Accumulation of abnormal proteins and endoplasmic reticulum stress accompany neurodegenerative diseases including Huntington's disease. We show that the expression of mutant huntingtin proteins with extended polyglutamine repeats differentially affected endoplasmic reticulum signaling cascades linked to the inositol-requiring enzyme-1 (IRE1) pathway. Thus, the p38 and c-Jun N-terminal kinase pathways were activated, while the levels of the nuclear factor-kappaB-p65 (NF-kappaB-p65) protein decreased. Downregulation of NF-kappaB signaling was linked to decreased antioxidant levels, increased oxidative stress, and enhanced cell death. Concomitantly, calpain was activated, and treatment with calpain inhibitors restored NF-kappaB-p65 levels and increased cell viability. The calpain regulator, calpastatin, was low in cells expressing mutant huntingtin, and overexpression of calpastatin counteracted the deleterious effects caused by N-terminal mutant huntingtin proteins. These results show that calpastatin and an altered NF-kappaB-p65 signaling are crucial factors involved in oxidative stress and cell death mediated by mutant huntingtin proteins.

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Section: Introductionmentioning

confidence: 99%

Downregulation of NF-κB signaling by mutant huntingtin proteins induces oxidative stress and cell death

Reijonen

Kukkonen

Hyrskyluoto

et al. 2010

Cell. Mol. Life Sci.

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“…Neuropathologically, the main HD hallmark is the selective loss of GABAergic medium spiny neurons in the striatum. Death of the patients occurs around 15 years after disease onset [for review, see [2]]. Wild-type (WT) Htt is ubiquitously expressed and seems to play an important role in cell survival [for review, see [2]; [3]].…”

Section: Introductionmentioning

confidence: 99%

“…Death of the patients occurs around 15 years after disease onset [for review, see [2]]. Wild-type (WT) Htt is ubiquitously expressed and seems to play an important role in cell survival [for review, see [2]; [3]]. The mutation has been suggested to alter WT Htt function and to promote a gain of function of full-length (FL)-mHtt and/or of its short N-terminal fragments [4,5].…”

Section: Introductionmentioning

confidence: 99%

Overexpression of BDNF and Full-Length TrkB Receptor Ameliorate Striatal Neural Survival in Huntington's Disease

Silva

Naia²,

Domínguez³

et al. 2015

Neurodegener Dis

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Background: Several cellular mechanisms have been proposed to explain the pathogenesis of Huntington's disease (HD), including the lack of striatal brain-derived neurotrophic factor (BDNF). Thus, by preferentially binding to tropomyosin receptor kinase B (TrkB) receptor, BDNF is an important neurotrophin implicated in striatal neuronal survival. Objective: To study the influence of BDNF and TrkB receptors in intracellular signaling pathways and caspase-3 activation in HD striatal cells. Methods: HD mutant knockin and wild-type striatal cells were transduced with preproBDNF or full-length TrkB receptors to analyze BDNF processing, AKT and extracellular signal-regulated kinase (ERK) activation and the activity of caspase-3 in the absence or presence of staurosporine (STS). Results: HD mutant cells transduced with preproBDNF-mCherry (mCh) expressed similar levels of pro- and mature BDNF compared to WT cells, but HD cells released lower levels of pro- and mature BDNF. Despite this, BDNF-mCh overexpression rescued decreased AKT phosphorylation and reduced the caspase-3 activation observed in HD cells. Activated ERK was also enhanced in HD BDNF-mCh/TrkB-eGFP receptor co-cultures. Of relevance, overexpression of TrkB-eGFP in HD cells decreased caspase-3 activation, and stimulation of TrkB-eGFP-transduced mutant cells with recombinant human BDNF reduced both basal and STS-induced caspase-3 activation. Conclusion: The results highlight the importance of BDNF-induced TrkB receptor signaling in rescuing HD-mediated apoptotic features in striatal cells.

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“…Huntington's Chorea is characterized by uncoordinated and awkward body movements, cognitive impairment and psychiatric symptoms (Gil and Rego 2008). The first transgenic rat model for Huntington's disease was generated by von Hörsten et al (2003).…”

Section: The Rat Models For Human Neurodegenerative Disordersmentioning

confidence: 99%

Beyond the Rat Models of Human Neurodegenerative Disorders

2009

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The rat is a model of choice in biomedical research for over a century. Currently, the rat presents the best "functionally" characterized mammalian model system. Despite this fact, the transgenic rats have lagged behind the transgenic mice as an experimental model of human neurodegenerative disorders. The number of transgenic rat models recapitulating key pathological hallmarks of Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, or human tauopathies is still limited. The reason is that the transgenic rats remain more difficult to produce than transgenic mice. The gene targeting technology is not yet established in rats due to the lack of truly totipotent embryonic stem cells and cloning technology. This extremely powerful technique has given the mouse a clear advantage over the rat in generation of new transgenic models. Despite these limitations, transgenic rats have greatly expanded the range of potential experimental approaches. The large size of rats permits intrathecal administration of drugs, stem cell transplantation, serial sampling of the cerebrospinal fluid, microsurgical techniques, in vivo nerve recordings, and neuroimaging procedures. Moreover, the rat is routinely employed to demonstrate therapeutic efficacy and to assess toxicity of novel therapeutic compounds in drug development. Here we suggest that the rat constitutes a slightly underestimated but perspective animal model well-suited for understanding the mechanisms and pathways underlying the human neurodegenerative disorders.

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Mechanisms of neurodegeneration in Huntington’s disease

Cited by 405 publications

References 275 publications

Downregulation of NF-κB signaling by mutant huntingtin proteins induces oxidative stress and cell death

Downregulation of NF-κB signaling by mutant huntingtin proteins induces oxidative stress and cell death

Overexpression of BDNF and Full-Length TrkB Receptor Ameliorate Striatal Neural Survival in Huntington's Disease

Beyond the Rat Models of Human Neurodegenerative Disorders

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