Neurogranin

Neurogranin

Neurogranin is a calmodulin-binding protein expressed primarily in the brain, particularly in dendritic spines, and participating in the protein kinase C signaling pathway. Neurogranin is the main postsynaptic protein regulating the availability of calmodulin, binding to it in the absence of calcium. Phosphorylation by protein kinase C lowers its binding ability. NRGN gene expression is controlled by thyroid hormones.

Human neurogranin consists of 78 amino acids.

One study tells of potential link of neurogranin gene to the heightened risk of schizophrenia in males, another study gives evidence of lowered neurogranin immunoreactivity in the brains of people suffering from schizophrenia.

Prior to its identification in the bovine and rat brain in 1991, neurogranin was known as a putative protein kinase C-phosphorylated protein named p17. Human neurogranin was cloned in 1997 and turned out to be 96% identical to the rat protein.


Çevik et al., determined whether serum neurogranin (NRGN), glial fibrillary acidic protein (GFAP), and calcium-binding protein S100 beta (S100B) levels are associated with traumatic intracranial lesions compared to computed tomography (CT) findings of patients with mild traumatic brain injury(mTBI).

The cross-sectional study cohort included 48 patients who were admitted to the Emergency Department with a complaint of mTBI, a Glasgow Coma Scale score of 14-15, and at least one symptom of head trauma (i.e., post-traumatic amnesianausea or vomiting, post-traumatic seizures, persistent headache, and transient loss of consciousness). Blood samples and CT scans were obtained for all patients within 4 h of injury. Age-matched patients without intracranial traumatic pathology (CT-) were recruited as a control group. Blood samples were measured for NRGN, GFAP, and S100B levels.

Of 48 patients, 24 were CT + and had significantly higher serum NRGN (5.79 vs. 2.95 ng/mL), GFAP (0.59 vs.0.36 ng/mL), and S100B (1.72 vs.0.73 μg/L) levels than those who were CT- (p = 0.001, p = 0.026, and p < 0.001, respectively). ROC curves showed that NRGN, GFAP, and S100B levels were sufficient to distinguish traumatic brain injury in patients with mTBI. At the cut-off value for NRGN of 1.87 ng/mL, sensivity was 83.3%, and specificity was 58.3%. At the cut-off value for GFAP of 0.23 ng/mL, sensivity was 75% and specificity was 62.5%. The optimal cut-off value for S100B was 0.47 μg/L (95.8% sensitivity and 62.5% specificity).

This is the first study to evaluate NRGN in human serum after mTBI. They confirmed that NRGN levels were significantly higher in CT + patients than CT- patients in the mTBI patient population. Future studies of larger populations and different age groups (especially pediatric) can help reduce the number of CT scans as a reliable and noninvasive diagnostic tool for evaluating NRGN protein levels in mTBI patients with a low probability of intracranial lesion1).


The early molecular response to severe traumatic brain injury (TBI) was evaluated using biopsies of structurally normal-appearing cortex, obtained at location for intracranial pressure (ICP) monitoring, from 16 severe TBI patients. Mass spectrometry (MS; label free and stable isotope dimethyl labeling) quantitation proteomics showed a strikingly different molecular pattern in TBI in comparison to cortical biopsies from 11 idiopathic normal pressure hydrocephalus patients. Diffuse TBI showed increased expression of peptides related to neurodegeneration (Tau and Fascin, p < 0.05), reduced expression related to antioxidant defense (Glutathione S-transferase Mu 3, Peroxiredoxin-6, Thioredoxin-dependent peroxide reductase; p < 0.05) and increased expression of potential biomarkers (e.g. Neurogranin, Fatty acid-binding protein, heart p < 0.05) compared to focal TBI. Proteomics of human brain biopsies displayed considerable molecular heterogeneity among the different TBI subtypes with consequences for the pathophysiology and development of targeted treatments for TBI 2).


The CSF levels of the synaptic marker neurogranin offer diagnostic and prognostic utility for early symptomatic AD that is comparable to other CSF markers of AD. Importantly, CSF neurogranin complements the collective ability of these markers to predict future cognitive decline in cognitively normal individuals and, therefore, will be a useful addition to the current panel of AD biomarkers 3).

Abnormal plasma NDE levels of P-tau, Aβ1-42, neurogranin, and REST accurately predict conversion of MCI to AD dementia. Plasma NDEs from demented patients seeded tau aggregation and induced AD-like neuropathology in normal mouse CNS 4).


Eight brain-derived proteins were evaluated regarding their potential for further development as a blood-based biomarker for malignant gliomas. Plasma levels for glial fibrillary acidic protein, neurogranin, brain-derived neurotrophic factor, intracellular adhesion molecule 5, metallothionein-3, beta-synuclein, S100 and neuron specific enolase were tested in plasma of 23 patients with high-grade gliomas (WHO grade IV), 11 low-grade gliomas (WHO grade II), and 15 healthy subjects. Compared to the healthy controls, none of the proteins appeared to be specific for glioblastomas. However, the data are suggestive of higher protein levels in gliosarcomas (n = 2), which may deserve further exploration 5).


Guadaño-Ferraz et al., investigated neurogranin expression in pyramidal cortical neurons and interneurons of the motor and somatosensory cortex of normal Macaca fascicularis by means of double immunofluorescence and with techniques that combine immunohistochemistry and radioactive in situ hybridization. We show that RC3 is expressed in virtually all pyramidal neurons and spiny stellate neurons of neocortical areas 4, 3b, 1, 2, 5, 7, and SII, but not in the majority of cortical interneurons. RC3 protein and mRNA are tightly colocalized with the alpha subunit of CaM kinase II and the 200-kD, nonphosphorylated neurofilament, whereas they are absent from cells expressing the 27-kD, vitamin D-dependent calbindin and parvalbumin. In order to investigate possible activity-dependent regulation of the expression of RC3, we compared these results with those obtained from monkeys subjected to chronic peripheral cutaneous denervation of the first finger. We found that the pattern of distribution of RC3 in motor and somatosensory cortices after nerve cut did not differ from normal 6).

References

1)

Çevik S, Özgenç MM, Güneyk A, Evran Ş, Akkaya E, Çalış F, Katar S, Soyalp C, Hanımoğlu H, Kaynar MY. NRGN, S100B and GFAP levels are significantly increased in patients with structural lesions resulting from mild traumatic brain injuries. Clin Neurol Neurosurg. 2019 Jun 17;183:105380. doi: 10.1016/j.clineuro.2019.105380. [Epub ahead of print] PubMed PMID: 31234132.
2)

Abu Hamdeh S, Shevchenko G, Mi J, Musunuri S, Bergquist J, Marklund N. Proteomic differences between focal and diffuse traumatic brain injury in human brain tissue. Sci Rep. 2018 May 1;8(1):6807. doi: 10.1038/s41598-018-25060-0. PubMed PMID: 29717219; PubMed Central PMCID: PMC5931620.
3)

Tarawneh R, D’Angelo G, Crimmins D, Herries E, Griest T, Fagan AM, Zipfel GJ, Ladenson JH, Morris JC, Holtzman DM. Diagnostic and Prognostic Utility of the Synaptic Marker Neurogranin in Alzheimer Disease. JAMA Neurol. 2016 May 1;73(5):561-71. doi: 10.1001/jamaneurol.2016.0086. PubMed PMID: 27018940; PubMed Central PMCID: PMC4861689.
4)

Winston CN, Goetzl EJ, Akers JC, Carter BS, Rockenstein EM, Galasko D, Masliah E, Rissman RA. Prediction of conversion from mild cognitive impairment to dementia with neuronally derived blood exosome protein profile. Alzheimers Dement (Amst). 2016 May 7;3:63-72. doi: 10.1016/j.dadm.2016.04.001. eCollection 2016. PubMed PMID: 27408937; PubMed Central PMCID: PMC4925777.
5)

Lange RP, Everett A, Dulloor P, Korley FK, Bettegowda C, Blair C, Grossman SA, Holdhoff M. Evaluation of eight plasma proteins as candidate blood-based biomarkers for malignant gliomas. Cancer Invest. 2014 Oct;32(8):423-9. doi: 10.3109/07357907.2014.933237. Epub 2014 Jul 14. PubMed PMID: 25019213; PubMed Central PMCID: PMC4322939.
6)

Guadaño-Ferraz A, Viñuela A, Oeding G, Bernal J, Rausell E. RC3/neurogranin is expressed in pyramidal neurons of motor and somatosensory cortex in normal and denervated monkeys. J Comp Neurol. 2005 Dec 26;493(4):554-70. PubMed PMID: 16304627.

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