Neuronatin-mediated Aberrant Calcium Signaling and Endoplasmic Reticulum Stress Underlie Neuropathology in Lafora Disease

Sharma, Jaiprakash; Mukherjee, Diptendu; Rao, Shobini L.; Iyengar, Soumya; Shankar, Susarla Krishna; Satishchandra, Parthasarathy; Jana, Nihar Ranjan

doi:10.1074/jbc.m112.416180

Cited by 44 publications

(37 citation statements)

References 48 publications

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“…Accordingly, the ectopic expression of Nnat in cultured neuronal cells results in increased intracellular Ca(2+), endoplasmic reticulum stress, proteasomal dysfunction and cell death. 35 In our experiments, Nnat levels appear significantly higher both in Foxg1+/ − whole brain and in silenced hippocampal neurons, strongly suggesting that this gene is directly or indirectly regulated by Foxg1.…”

Section: Discussionmentioning

confidence: 61%

“…In adult brain, Nnat is predominantly expressed in parvalbumin-positive GABAergic interneurons. Its levels are increased and accumulated as insoluble aggregates in the cortical area of patients with Lafora disease, a progressive and fatal neurodegenerative disease due to variants in Laforin and Malin genes; 35 in this condition, Nnat accumulation is accompanied by a dramatic loss of parvalbumin-positive GABAergic interneurons. Accordingly, the ectopic expression of Nnat in cultured neuronal cells results in increased intracellular Ca(2+), endoplasmic reticulum stress, proteasomal dysfunction and cell death.…”

Section: Discussionmentioning

confidence: 99%

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Altered expression of neuropeptides in FoxG1-null heterozygous mutant mice

et al. 2015

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Foxg1 gene encodes for a transcription factor essential for telencephalon development in the embryonic mammalian forebrain. Its complete absence is embryonic lethal while Foxg1 heterozygous mice are viable but display microcephaly, altered hippocampal neurogenesis and behavioral and cognitive deficiencies. In order to evaluate the effects of Foxg1 alteration in adult brain, we performed expression profiling in total brains from Foxg1+/ − heterozygous mutants and wild-type littermates. We identified statistically significant differences in expression levels for 466 transcripts (Po0.001), 29 of which showed a fold change ≥ 1.5. Among the differentially expressed genes was found a group of genes expressed in the basal ganglia and involved in the control of movements. A relevant (three to sevenfold changes) and statistically significant increase of expression, confirmed by qRT-PCR, was found in two highly correlated genes with expression restricted to the hypothalamus: Oxytocin (Oxt) and Arginine vasopressin (Avp). These neuropeptides have an important role in maternal and social behavior, and their alteration is associated with impaired social interaction and autistic behavior. In addition, Neuronatin (Nnat) levels appear significantly higher both in Foxg1+/ − whole brain and in hippocampal neurons after silencing Foxg1, strongly suggesting that it is directly or indirectly repressed by Foxg1. During fetal and neonatal brain development, Nnat may regulate neuronal excitability, receptor trafficking and calcium-dependent signaling and, in the adult brain, it is predominantly expressed in parvalbumin-positive GABAergic interneurons. Overall, these results implicate the overexpression of a group of neuropeptides in the basal ganglia, hypothalamus, cortex and hippocampus in the pathogenesis FOXG1 behavioral impairments.

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Section: Discussionmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Altered expression of neuropeptides in FoxG1-null heterozygous mutant mice

et al. 2015

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“…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: 83%

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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“…Knowing that NNAT has a strong tendency to misfold and form cellular inclusions driving apoptotic cell death (Joseph, 2014), it is not surprising that the rodent ADRP models, experiencing severe cellular stress and apoptotic photoreceptor cell death (Kunte et al, 2012; Shinde et al, 2012) demonstrate partial accumulation of NNAT in the ONL of the retina. Possibly, the observed partial retention of NNAT is due to its ability to regulate Ca 2+ signaling and antagonize the SERCA2b pump (Sharma et al, 2013). Thus, in our previous study, we have found that both the aberrant Ca 2+ signaling and compromised SERCA2b activity were detected in S334ter and P23H RHO transgenic retinas (Shinde et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, Mzhavia et al have also described the pathophysiological role of NNAT in diabetic vascular disease and have demonstrated NNAT-induced upregulation of NF-kB, increase in inflammatory gene expression, and the promotion of p38 and Jun-N signaling molecules in endothelial cells (Mzhavia et al, 2008). In patients with Lafora disease, NNAT has been reported to contribute to neuro pathogenesis by mediating aberrant Ca 2+ signaling, the activation of endoplasmic reticulum (ER) stress, and the formation of aggregates called Lafora bodies (Sharma et al, 2013). …”

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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Neuronatin-mediated Aberrant Calcium Signaling and Endoplasmic Reticulum Stress Underlie Neuropathology in Lafora Disease

Cited by 44 publications

References 48 publications

Altered expression of neuropeptides in FoxG1-null heterozygous mutant mice

Altered expression of neuropeptides in FoxG1-null heterozygous mutant mice

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

Neuronatin is a stress-responsive protein of rod photoreceptors

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