Epilepsy, one of the most common neurological disorders, is characterized by spontaneous recurrent seizures. Temporal lobe epilepsy (TLE) is one of the most common medically intractable seizure ...disorders. Traf2-and NcK-interacting kinase (TNIK) has recently attracted attention as a critical modulation target of many neurological and psychiatric disorders, but its role in epilepsy remains unclear. In this study, we hypothesized the involvement of TNIK in epilepsy and investigated TNIK expression in patients with intractable TLE and in a pilocarpine-induced rat model of epilepsy by western blotting, immunofluorescence, and immunohistochemistry. A pentylenetetrazole (PTZ)-induced epilepsy rat model was used to determine the effect of the TNIK inhibitor NCB-0846 on behavioral manifestations of epilepsy. Coimmunoprecipitation (Co-IP)/mass spectrometry (MS) was used to identify the potential mechanism. Through Co-IP, we detected and confirmed the main potential TNIK interactors. Subcellular fractionation was used to establish the effect of NCB-0846 on the expression of the main interactors in postsynaptic density (PSD) fractions. We found that TNIK was primarily located in neurons and decreased significantly in epilepsy model rats and TLE patients compared with controls. NCB-0846 delayed kindling progression and decreased seizure severity. Co-IP/MS identified 63 candidate TNIK interactors in rat hippocampi, notably CaMKII. Co-IP showed that TNIK might correlate with endogenous GRIA1, SYN2, PSD-95, CaMKIV, GABRG1, and GABRG2. In addition, the significant decrease in GRIA1 in hippocampal total lysate and PSDs after NCB-0846 treatment might help modify the progression of PTZ kindling. Our results suggest that TNIK contributes to epileptic pathology and is a potential antiepileptic drug target.
Autosomal-recessive dopa-responsive dystonia (DRD) is a rare clinical disorder presenting as bradykinesia, dystonia, tremor and even severe encephalopathy, and caused by tyrosine hydroxylase ...deficiency (THD). We report a case of compound heterozygous mutations in the TH gene in a Chinese family with autosomal-recessive DRD herein.
A 16-month-old Chinese boy presented with symptoms of movement disorder and growth retardation in his infant period.
The genetic test revealed compound heterozygous mutations in the TH gene at c.457C>T and c.698G>A, which are pathogenic of DRD.
The patient was administrated low-dose levodopa.
The treatment resulted in the substantial improvement of dystonia. His long-term neurological outcome need follow-up for years.
Gene mutation analysis is helpful and necessary to diagnose DRD and has important guiding significance for the subsequent treatment.
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