The fetal and neonatal brain protein neuronatin protects PC12 cells against certain types of toxic insult

Zheng, Shuang; Chou, Alice H; Jimenez, Amie L; Khodadadi, Omid; Son, Sarah A.; Melega, William P.; Howard, Bruce D.

doi:10.1016/s0165-3806(02)00348-6

Cited by 20 publications

(14 citation statements)

References 32 publications

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“…Compared to HBT results which show that NNAT expression declines during neuronal development and reaches the bottom after birth, NNAT mRNA level in FXS-iPSC derived neurons is modestly high and spikes at D18 and D50. NNAT, an imprinted gene expressed from paternal allele, is down-regulated when PC12 cells undergo neuronal differentiation (Joseph et al, 1996;Zheng et al, 2002). Since high level of NNAT aggregates are found in Lafora disease (Sharma et al, 2011;Sharma et al, 2013) and phenylketonuria (Surendran et al, 2005), our data suggested that elevated NNAT expression may hinder the neuronal development in FXS patients.…”

Section: Discussionmentioning

confidence: 70%

Integrated transcriptome analysis of human iPS cells derived from a fragile X syndrome patient during neuronal differentiation

Lü

Chen

Feng

et al. 2016

Sci. China Life Sci.

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Fragile X syndrome (FXS) patients carry the expansion of over 200 CGG repeats at the promoter of fragile X mental retardation 1 (FMR1), leading to decreased or absent expression of its encoded fragile X mental retardation protein (FMRP). However, the global transcriptional alteration by FMRP deficiency has not been well characterized at single nucleotide resolution, i.e., RNA-seq. Here, we performed in-vitro neuronal differentiation of human induced pluripotent stem (iPS) cells that were derived from fibroblasts of a FXS patient (FXS-iPSC). We then performed RNA-seq and examined the transcriptional misregulation at each intermediate stage during in-vitro differentiation of FXS-iPSC into neurons. After thoroughly analyzing the transcriptomic data and integrating them with those from other platforms, we found up-regulation of many genes encoding TFs for neuronal differentiation (WNT1, BMP4, POU3F4, TFAP2C, and PAX3), down-regulation of potassium channels (KCNA1, KCNC3, KCNG2, KCNIP4, KCNJ3, KCNK9, and KCNT1) and altered temporal regulation of SHANK1 and NNAT in FXS-iPSC derived neurons, indicating impaired neuronal differentiation and function in FXS patients. In conclusion, we demonstrated that the FMRP deficiency in FXS patients has significant impact on the gene expression patterns during development, which will help to discover potential targeting candidates for the cure of FXS symptoms.

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Section: Discussionmentioning

confidence: 70%

Integrated transcriptome analysis of human iPS cells derived from a fragile X syndrome patient during neuronal differentiation

Lü

Chen

Feng

et al. 2016

Sci. China Life Sci.

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“…Previous data in the neuron-like PC12 cell line suggests potential neuroprotective effects of NNAT [36], leading us to hypothesize that it might do the same in HD model systems.…”

Section: Resultsmentioning

confidence: 90%

Decreased Striatal RGS2 Expression Is Neuroprotective in Huntington's Disease (HD) and Exemplifies a Compensatory Aspect of HD-Induced Gene Regulation

2011

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BackgroundThe molecular phenotype of Huntington's disease (HD) is known to comprise highly reproducible changes in gene expression involving striatal signaling genes. Here we test whether individual changes in striatal gene expression are capable of mitigating HD-related neurotoxicity.Methodology/Principal FindingsWe used protein-encoding and shRNA-expressing lentiviral vectors to evaluate the effects of RGS2, RASD2, STEP and NNAT downregulation in HD. Of these four genes, only RGS2 and RASD2 modified mutant htt fragment toxicity in cultured rat primary striatal neurons. In both cases, disease modulation was in the opposite of the predicted direction: whereas decreased expression of RGS2 and RASD2 was associated with the HD condition, restoring expression enhanced degeneration of striatal cells. Conversely, silencing of RGS2 or RASD2 enhanced disease-related changes in gene expression and resulted in significant neuroprotection. These results indicate that RGS2 and RASD2 downregulation comprises a compensatory response that allows neurons to better tolerate huntingtin toxicity. Assessment of the possible mechanism of RGS2-mediated neuroprotection showed that RGS2 downregulation enhanced ERK activation. These results establish a novel link between the inhibition of RGS2 and neuroprotective modulation of ERK activity.ConclusionsOur findings both identify RGS2 downregulation as a novel compensatory response in HD neurons and suggest that RGS2 inhibition might be considered as an innovative target for neuroprotective drug development.

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“…Thus, Zheng et al have proposed the protective role for NNAT during neuronal development from the external toxic insults (Zheng et al, 2002), while other studies conducted with non-neuronal cells suggested that NNAT could act as an intracellular Ca 2+ modulator (Suh et al, 2005; Poon et al, 2006; Joe et al, 2008). In addition to maintaining cellular homeostasis, NNAT can play a role in pathological processes.…”

Section: Introductionmentioning

confidence: 99%

Neuronatin is a stress-responsive protein of rod photoreceptors

et al. 2016

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Neuronatin (NNAT) is a small transmembrane proteolipid that is highly expressed in the embryonic developing brain and several other peripheral tissues. This study is the first to provide evidence that NNAT is detected in the adult retina of various adult rod-dominant mammals, including wild-type (WT) rodents, transgenic rodents expressing mutant S334ter, P23H, or T17M rhodopsin, non-human primates, humans, and cone-dominant tree shrews. Immunohistochemical and quantitative real time polymerase chain reaction (qRT-PCR) analyses were applied to detect NNAT. Confocal microscopy analysis revealed that NNAT immunofluorescence is restricted to the outer segments (OSs) of photoreceptors without evidence of staining in other retinal cell types across all mammalian species. Moreover, in tree shrew retinas, we found NNAT to be co-localized with rhodopsin, indicating its predominant expression in rods. The rod-derived expression of NNAT was further confirmed by qRT-PCR in isolated rod photoreceptor cells. We also used these cells to mimic cellular stress in transgenic retinas by treating them with the endoplasmic reticulum stress inducer, tunicamycin. Thus, our data revealed accumulation of NNAT around the nucleus as compared to dispersed localization of NNAT within control cells. This distribution coincided with the partial intracellular mislocalization of NNAT to the outer nuclear layer observed in transgenic retinas. In addition, stressed retinas demonstrated an increase of NNAT mRNA and protein levels. Therefore, our study demonstrated that NNAT is a novel stress-responsive protein with a potential structural and/or functional role in adult mammalian retinas.

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The fetal and neonatal brain protein neuronatin protects PC12 cells against certain types of toxic insult

Cited by 20 publications

References 32 publications

Integrated transcriptome analysis of human iPS cells derived from a fragile X syndrome patient during neuronal differentiation

Integrated transcriptome analysis of human iPS cells derived from a fragile X syndrome patient during neuronal differentiation

Decreased Striatal RGS2 Expression Is Neuroprotective in Huntington's Disease (HD) and Exemplifies a Compensatory Aspect of HD-Induced Gene Regulation

Neuronatin is a stress-responsive protein of rod photoreceptors

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