Mutant Huntingtin Causes a Selective Decrease in the Expression of Synaptic Vesicle Protein 2C

Huntington＇s disease （HD） is a neurodegenera- tive disease caused by a polyglutamine expansion in the huntingtin （Htt） protein. Mutant Htt causes synaptic transmission dysfunctions by interfering in the expression of synaptic proteins, leading to early HD symptoms. Synaptic vesicle proteins 2 （SV2s）, a family of synaptic vesicle proteins including 3 members, SV2A, SV2B, and SV2C, plays important roles in synaptic physiology. Here, we investigated whether the expression of SV2s is affected by mutant Htt in the brains of HD transgenic （TG） mice and Neuro2a mouse neuroblastoma cells （N2a cells） expressing mutant Htt. Western blot analysis showed that the protein levels of SV2A and SV2B were not signifi- cantly changed in the brains of HD TG mice expressing mutant Htt with 82 glutamine repeats. However, in the TG mouse brain there was a dramatic decrease in the protein level of SV2C, which has a restricted distribution pattern in regions particularly vulnerable in HD. Immunostaining revealed that the immunoreactivity of SV2C was progres- sively weakened in the basal ganglia and hippocampus of TG mice. RT-PCR demonstrated that the mRNA level of SV2C progressively declined in the TG mouse brain without detectable changes in the mRNA levels of SV2A and SV2B, indicating that mutant Htt selectively inhibits the transcriptional expression of SV2C. Furthermore, we found that only SV2C expression was progressively inhibited in N2a cells expressing a mutant Htt containing 120 glutamine repeats. These findings suggest that the synaptic dysfunction in HD results from the mutant Htt- mediated inhibition of SV2C transcriptional expression. These data also imply that the restricted distribution and decreased expression of SV2C contribute to the brain region-selective pathology of HD.

Development of SV2A Ligands for Epilepsy Treatment:A Review of Levetiracetam,Brivaracetam,and Padsevonil

Epilepsy is a common neurological disorder that is primarily treated with antiseizure medications(ASMs).Although dozens of ASMs are available in the clinic,approximately 30%of epileptic patients have medically refractory seizures;other limitations in most traditional ASMs include poor tolerability and drug-drug interactions.Therefore,there is an urgent need to develop alternative ASMs.Levetiracetam(LEV)is a first-line ASM that is well tolerated,has promising efficacy,and has little drug-drug interaction.Although it is widely accepted that LEV acts through a unique therapeutic target synaptic vesicle protein(SV)2A,the molecular basis of its action remains unknown.Even so,the next-generation SV2A ligands against epilepsy based on the structure of LEV have achieved clinical success.This review highlights the research and development(R&D)process of LEV and its analogs,brivaracetam and padsevonil,to provide ideas and experience for the R&D of novel ASMs.