The neuroprotective effects of cyclin-dependent kinase-5 inhibition in mice with Niemann-Pick disease type C |
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Authors: | Youguo Hao Dengji Pan Min Zhang Jinzhi Xu Linjuan Li Jiajun Wei Xuezhen Wang |
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Institution: | Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan Wuhan 430030, China |
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Abstract: | Summary In order to investigate the neuroprotective effects of cyclin-dependent kinase-5 (cdk-5) inhibition in mice with Niemann-Pick
disease type C (NPC) (npc−/−), recombinant adeno-associated virus (rAAV) carrying the small interfering RNA (siRNA) specific for cdk-5 gene was injected
into 3-day-old npc−/− mice intracerebroventricularly. The rAAV-GFP-injected age-matched npc−/− mice and non-surgery age-matched npc−/− mice were employed as controls (n=6−10/group). From the 4th to 8th week after the treatment, mice were weighed, and evaluated for limb motor activity by using
the coat hanger test once a week. Eight-week-old npc−/− mice were sacrificed by decapitation, and brains were quickly dissected and halved sagittally. Immunohistochemistry, Western
blotting, and HE staining were used to evaluate the neuropathology in npc−/− mice. The results showed that rAAV-cdk-5-siRNA-GFP significantly reduced the number of axonal spheroids, delayed the death
of Purkinje neurons, ameliorated motor defects in npc−/− mice, and significantly attenuated the hyperphosphorylation of tau proteins. These data suggested that inhibition of cdk-5
activity has neuroprotective effect on neurons in NPC mice.
Youguo HAO and Dengji PAN contributed equally to this study.
This study was supported by a grant from the National Natural Sciences Foundation of China (No. 30400141, 30670737). |
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Keywords: | Niemalm-Pick disease type C cyclin dependent kinase-5 cytoskeleton hyperphos-phorylation small interfering RNA recombinant adeno-associated virus |
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