Polyglutamine toxicity induces rod photoreceptor division, morphological transformation or death in Spinocerebellar ataxia 7 mouse retina

Yéfimova, Marina; Messaddeq, Nadia; Karam, Alice; Jacquard, Carine; Weber, C. R.; Jonet, Laurent; Wolfrum, Uwe; Jeanny, Jean-Claude; Trottier, Yvon

doi:10.1016/j.nbd.2010.06.005

Cited by 22 publications

(35 citation statements)

References 49 publications

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“…This model is particularly striking because the cornea cells on the same eye section present TUNEL positive cells indicating that the lack of TUNEL labelling in the retina is not a methodological failure. In this paradigm, but also in others presenting the same behaviour [5], we found that the enzyme involved in DNA degradation is L-DNase II [6][7].…”

Section: Introductory Statementsupporting

confidence: 65%

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On the use of an appropriate TdT-mediated dUTP–biotin nick end labeling assay to identify apoptotic cells

Lebon

Rodriguez

Zaoui

et al. 2015

Analytical Biochemistry

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Apoptosis is an essential cellular mechanism involved in many processes such as embryogenesis, metamorphosis, and tissue homeostasis. DNA fragmentation is one of the key markers of this form of cell death. DNA fragmentation is executed by endogenous endonucleases such as caspase-activated DNase (CAD) in caspase-dependent apoptosis. The TUNEL (TdT-mediated dUTP-biotin nick end labeling) technique is the most widely used method to identify apoptotic cells in a tissue or culture and to assess drug toxicity. It is based on the detection of 3'-OH termini that are labeled with dUTP by the terminal deoxynucleotidyl transferase. Although the test is very reliable and sensitive in caspase-dependent apoptosis, it is completely useless when cell death is mediated by pathways involving DNA degradation that generates 3'-P ends as in the LEI/L-DNase II pathway. Here, we propose a modification in the TUNEL protocol consisting of a dephosphorylation step prior to the TUNEL labeling. This allows the detection of both types of DNA breaks induced during apoptosis caspase-dependent and independent pathways, avoiding underestimating the cell death induced by the treatment of interest.

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Section: Introductory Statementsupporting

confidence: 65%

“…Here we show an example with genetic retinal degeneration [5]. In the SCA7 mice model, we observe a reduction of the photoreceptor nuclear layer leading to a decrease in retinal functionality {Yefimova, 2010 #631}.…”

Section: Resultsmentioning

confidence: 93%

On the use of an appropriate TdT-mediated dUTP–biotin nick end labeling assay to identify apoptotic cells

Lebon

Rodriguez

Zaoui

et al. 2015

Analytical Biochemistry

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“…13). Additional work with different disease models is beginning to show evidence for retinal remodeling in a number of animal models not traditionally associated with retinal disease, including spinocerebellar ataxia [94]. …”

Section: Human Diseases and Animal Models Of Retinal Degeneration Thamentioning

confidence: 99%

Retinal remodeling

et al. 2012

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Retinal photoreceptor degeneration takes many forms. Mutations in rhodopsin genes or disorders of the retinal pigment epithelium, defects in the adenosine triphosphate binding cassette transporter, ABCR gene defects, receptor tyrosine kinase defects, ciliopathies and transport defects, defects in both transducin and arrestin, defects in rod cyclic guanosine 3′,5′-monophosphate phosphodiesterase, peripherin defects, defects in metabotropic glutamate receptors, synthetic enzymatic defects, defects in genes associated with signaling, and many more can all result in retinal degenerative disease like retinitis pigmentosa (RP) or RP-like disorders. Age-related macular degeneration (AMD) and AMD-like disorders are possibly due to a constellation of potential gene targets and gene/gene interactions, while other defects result in diabetic retinopathy or glaucoma. However, all of these insults as well as traumatic insults to the retina result in retinal remodeling. Retinal remodeling is a universal finding subsequent to retinal degenerative disease that results in deafferentation of the neural retina from photoreceptor input as downstream neuronal elements respond to loss of input with negative plasticity. This negative plasticity is not passive in the face of photoreceptor degeneration, with a phased revision of retinal structure and function found at the molecular, synaptic, cell, and tissue levels involving all cell classes in the retina, including neurons and glia. Retinal remodeling has direct implications for the rescue of vision loss through bionic or biological approaches, as circuit revision in the retina corrupts any potential surrogate photoreceptor input to a remnant neural retina. However, there are a number of potential opportunities for intervention that are revealed through the study of retinal remodeling, including therapies that are designed to slow down photoreceptor loss, interventions that are designed to limit or arrest remodeling events, and oplogenetic approaches that target appropriate classes of neurons in the remnant neural retina.

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“…In a SCA1 mouse model, specific genes involved in glutamate signaling functions were deregulated in Purkinje cells, one major target of the disease [14]. More strikingly, in a mouse model recapitulating the retinal degeneration affecting SCA7 patients, the retinopathy correlated with a global repression of genes specifically involved in photoreceptor function and morphogenesis, suggesting an alteration of the neuronal differentiation program [15], [16].…”

Section: Introductionmentioning

confidence: 98%

Transcriptional Activation of REST by Sp1 in Huntington's Disease Models

et al. 2010

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In Huntington's disease (HD), mutant huntingtin (mHtt) disrupts the normal transcriptional program of disease neurons by altering the function of several gene expression regulators such as Sp1. REST (Repressor Element-1 Silencing Transcription Factor), a key regulator of neuronal differentiation, is also aberrantly activated in HD by a mechanism that remains unclear. Here, we show that the level of REST mRNA is increased in HD mice and in NG108 cells differentiated into neuronal-like cells and expressing a toxic mHtt fragment. Using luciferase reporter gene assay, we delimited the REST promoter regions essential for mHtt-mediated REST upregulation and found that they contain Sp factor binding sites. We provide evidence that Sp1 and Sp3 bind REST promoter and interplay to fine-tune REST transcription. In undifferentiated NG108 cells, Sp1 and Sp3 have antagonistic effect, Sp1 acting as an activator and Sp3 as a repressor. Upon neuronal differentiation, we show that the amount and ratio of Sp1/Sp3 proteins decline, as does REST expression, and that the transcriptional role of Sp3 shifts toward a weak activator. Therefore, our results provide new molecular information to the transcriptional regulation of REST during neuronal differentiation. Importantly, specific knockdown of Sp1 abolishes REST upregulation in NG108 neuronal-like cells expressing mHtt. Our data together with earlier reports suggest that mHtt triggers a pathogenic cascade involving Sp1 activation, which leads to REST upregulation and repression of neuronal genes.

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Polyglutamine toxicity induces rod photoreceptor division, morphological transformation or death in Spinocerebellar ataxia 7 mouse retina

Cited by 22 publications

References 49 publications

On the use of an appropriate TdT-mediated dUTP–biotin nick end labeling assay to identify apoptotic cells

On the use of an appropriate TdT-mediated dUTP–biotin nick end labeling assay to identify apoptotic cells

Retinal remodeling

Transcriptional Activation of REST by Sp1 in Huntington's Disease Models

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