Growth‐associated protein 43 and progressive epilepsy in cortical dysplasia

Zhang, Ying; Najm, Imad; Nemes, Ashley D.; Pinheiro-Martins, Ana Paula; Alexopoulos, Andreas V.; González-Martínez, Jorge; Bingaman, William

doi:10.1002/acn3.69

Cited by 16 publications

(19 citation statements)

References 39 publications

(84 reference statements)

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“…In addition, GAP - 43 encoding for homonymous protein involved in axon growth is bound [86] and stabilized by HuR [76]. Importantly, GAP-43 is a marker for progressive epilepsy in patients with focal cortical dysplasia [87]. …”

Section: Hu Protein Familymentioning

confidence: 99%

mTOR and MAPK: from localized translation control to epilepsy

Pernice¹,

Schieweck²,

Kiebler³

et al. 2016

BMC Neurosci

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BackgroundEpilepsy is one of the most common neurological diseases characterized by excessive hyperexcitability of neurons. Molecular mechanisms of epilepsy are diverse and not really understood. All in common is the misregulation of proteins that determine excitability such as potassium and sodium channels as well as GABA receptors; which are all known as biomarkers for epilepsy. Two recently identified key pathways involve the kinases mechanistic target of rapamycin (mTOR) and mitogen-activated protein kinases (MAPK). Interestingly, mRNAs coding for those biomarkers are found to be localized at or near synapses indicating a local misregulation of synthesis and activity.ResultsResearch in the last decade indicates that RNA-binding proteins (RBPs) responsible for mRNA localization, stability and translation mediate local expression control. Among others, they are affected by mTOR and MAPK to guide expression of epileptic factors. These results suggest that mTOR/MAPK act on RBPs to regulate the fate of mRNAs, indicating a misregulation of protein expression at synapses in epilepsy.ConclusionWe propose that mTOR and MAPK regulate RBPs, thereby guiding the local expression of their target-mRNAs encoding for markers of epilepsy. Thus, misregulated mTOR/MAPK-RBP interplay may result in excessive local synthesis of ion channels and receptors thereby leading to hyperexcitability. Continuous stimulation of synapses further activates mTOR/MAPK pathway reinforcing their effect on RBP-mediated expression control establishing the basis for epilepsy. Here, we highlight findings showing the tight interplay between mTOR as well as MAPK with RBPs to control expression for epileptic biomarkers.

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Section: Hu Protein Familymentioning

confidence: 99%

mTOR and MAPK: from localized translation control to epilepsy

Pernice¹,

Schieweck²,

Kiebler³

et al. 2016

BMC Neurosci

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“…p = 0.47; Histology: n = 20 non-CD, n = 18 CD; Molecular biology: n = 28 non-CD, n = 27 CD). Sections stained with immunohistochemistry (IHC) for GAP-43 protein were randomized and qualitatively graded as previously described 14 . Bilateral somatosensory cortex images (A/P = −2.0 ± 0.2 mm) were taken and analyzed (two coronal slices, for a total of 4 images per rat).…”

Section: Resultsmentioning

confidence: 99%

“…The IHC staining intensity in the cortex was given a grade 2–8 based on neuronal rim staining (cell surface) and tubular punctate expression (intracellular) by two blinded investigators (AN and ZY). As previously reported, the scores were calculated based on the sum of qualitative grading of Rim and Tubular Punctate GAP-43 expression 14 . Rim Staining Value: 4 = more than 50% of neurons in the image positive for GAP-43 stained rim, 3 = more than 10% but less than 50%, 2 = about 5–10%, 1 = less than 5% of neurons; Tubular Punctate Staining Value: 4 = intensely dark, 3 = moderately dark, 2 = some punctate staining, 1 = no staining.…”

Section: Resultsmentioning

confidence: 99%

“…There is increasing evidence that cellular and neural networks at the local epileptic area extend beyond the lesion, which may explain why some surgical resections classically fail 12 , 13 . We have recently shown that the duration of epilepsy in patients with CD is correlated with increased expression of growth-associated protein 43 (GAP-43), a marker of axonal and synaptic growth 14 . GAP-43 is upregulated following stroke and traumatic brain injury 15 – 19 .…”

Section: Introductionmentioning

confidence: 99%

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Growth Associated Protein 43 (GAP-43) as a Novel Target for the Diagnosis, Treatment and Prevention of Epileptogenesis

Nemes

Ayasoufi

Zhang

et al. 2017

Sci Rep

Self Cite

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We previously showed increased growth associated protein 43 (GAP-43) expression in brain samples resected from patients with cortical dysplasia (CD), which was correlated with duration of epilepsy. Here, we used a rat model of CD to examine the regulation of GAP-43 in the brain and serum over the course of epileptogenesis. Baseline GAP-43 expression was higher in CD animals compared to control non-CD rats. An acute seizure increased GAP-43 expression in both CD and control rats. However, GAP-43 expression decreased by day 15 post-seizure in control rats, which did not develop spontaneous seizures. In contrast, GAP-43 remained up-regulated in CD rats, and over 50% developed chronic epilepsy with increased GAP-43 levels in their serum. GAP-43 protein was primarily located in excitatory neurons, suggesting its functional significance in epileptogenesis. Inhibition of GAP-43 expression by shRNA significantly reduced seizure duration and severity in CD rats after acute seizures with subsequent reduction in interictal spiking. Serum GAP-43 levels were significantly higher in CD rats that developed spontaneous seizures. Together, these results suggest GAP-43 as a key factor promoting epileptogenesis, a possible therapeutic target for treatment of progressive epilepsy and a potential biomarker for epilepsy progression in CD.

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“…Furthermore, phosphorylated ERK1/2 (p-ERK1/2) also seemed to play a crucial role in synapse reorganization by activating the transcription factor C-fos, which was involved not merely in repairing nerve trauma (e.g. nerve regeneration), but also in promoting axon growth and synaptic plasticity through targeting growth associated protein 43 (GAP-43) [18][19][20][21]. Therefore, we proposed a hypothesis that HTR6 may be able to stimulate epilepsy-induced MFS by activating Fyn, ERK1/2 and GAP-43 [21,22].…”

Section: Introductionmentioning

confidence: 99%

The Role of 5-HTR6 in Mossy Fiber Sprouting: Activating Fyn and p-ERK1/2 in Pilocarpine-Induced Chronic Epileptic Rats

Lin

Huang

Chen

et al. 2017

Cell Physiol Biochem

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Objective: Our primary objective is to verify whether 5-HTR6 is involved in the development of mossy fiber sprouting (MFS), and to determine how the progression of MFS is affected by 5-HTR6. Methods: A total of 90 male adult Sprague-Dawley rats were allocated into either the control group (n=36) or the epileptic group (n=54). Status epilepticus (SE) of rats was induced by the intraperitoneal (i.p.) injection of LiCl-pilocarpine. We conducted our experiments in two stages. The first stage involves equally dividing 36 epileptic rats into three groups with treatments of none, 5-HTR6 antagonist SB-27104 (SB) and vehicle DMSO. Then behavior and electroencephalogram (EEG) of rats were monitored by video-EEG. The second stage involves dividing 126 epileptic rats into seven groups with treatments of none, 10% DMSO, SB (100 µg/kg), Fyn antagonist PP 2 (50 µg/kg), p-ERK1/2 antagonist PD-98059 (30 µg/kg), SB (100 µg/ kg) + PP 2 (50 µg/kg); SB (100 µg/kg) + PD-98059 (30 µg/kg). We also treated 18 rats in the control group of the first stage with 100 µg/kg 5-HTR6 agonist WAY-181187 (WAY). MFS of rats was detected through the approach of Timm's staining. Finally, expressions of 5-HTR6, Fyn, p-ERK1/2 and GAP-3 were qualified and semi-quantified via western blotting or RT-PCR. Results: Induction of SE could stimulate formation of MFS and increased GAP-43 expressions. Expressions of 5-HTR6, Fyn and p-ERK1/2 were also up-regulated with increasing time after establishment of SE models. The development of MFS was remarkably inhibited by SB, PP 2 and PD. Compared to the single antagonist, such an inhibitory effect was enhanced by SB+PD or SB+PP. Moreover, treatment of healthy rats with WAY would contribute to up-regulated Fyn and p-ERK1/2 expressions, as well as development of MFS (P < 0.05). Suppression of Fyn triggered a down-regulating trend of p-ERK1/2 (P < 0.05), however, suppressed p-ERK1/2 did not have such a significant effect on Fyn expression. Conclusion: HTR6 may affect the progression of MFS by activating both p-ERK1/2 and Fyn, which further modulate the expression of GAP-43.W. Lin and W. Huang contributed equally to this work.

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Growth‐associated protein 43 and progressive epilepsy in cortical dysplasia

Cited by 16 publications

References 39 publications

mTOR and MAPK: from localized translation control to epilepsy

mTOR and MAPK: from localized translation control to epilepsy

Growth Associated Protein 43 (GAP-43) as a Novel Target for the Diagnosis, Treatment and Prevention of Epileptogenesis

The Role of 5-HTR6 in Mossy Fiber Sprouting: Activating Fyn and p-ERK1/2 in Pilocarpine-Induced Chronic Epileptic Rats

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