Peptide TFP5/TP5 derived from Cdk5 activator P35 provides neuroprotection in the MPTP model of Parkinson's disease

被引：36

作者：

Binukumar, B. K. ^{[1
]}

Shukla, Varsha ^{[1
]}

Amin, Niranjana D. ^{[1
]}

Grant, Philip ^{[1
]}

Bhaskar, M. ^{[1
]}

Skuntz, Susan ^{[1
]}

Steiner, Joseph ^{[1
]}

Pant, Harish C. ^{[1
]}

机构：

[1] NINDS, NIH, Bethesda, MD 20892 USA

来源：

MOLECULAR BIOLOGY OF THE CELL | 2015年 / 26卷 / 24期

基金：

美国国家卫生研究院;

关键词：

CYCLIN-DEPENDENT KINASE-5; NIGROSTRIATAL DOPAMINERGIC-NEURONS; ALZHEIMERS-DISEASE; MOUSE MODEL; MICROGLIAL ACTIVATION; TREATED MICE; CDK5-MEDIATED PHOSPHORYLATION; MITOCHONDRIAL DYSFUNCTION; TAU HYPERPHOSPHORYLATION; OXIDATIVE STRESS;

D O I：

10.1091/mbc.E15-06-0415

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Parkinson's disease (PD) is a chronic neurodegenerative disorder characterized by the loss of dopamine neurons in the substantia nigra, decreased striatal dopamine levels, and consequent extrapyramidal motor dysfunction. Recent evidence indicates that cyclin-dependent kinase 5 (Cdk5) is inappropriately activated in several neurodegenerative conditions, including PD. To date, strategies to specifically inhibit Cdk5 hyperactivity have not been successful without affecting normal Cdk5 activity. Previously we reported that TFP5 peptide has neuroprotective effects in animal models of Alzheimer's disease. Here we show that TFP5/TP5 selective inhibition of Cdk5/p25 hyperactivation in vivo and in vitro rescues nigrostriatal dopaminergic neurodegeneration induced by 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine (MPTP/MPP+) in a mouse model of PD. TP5 peptide treatment also blocked dopamine depletion in the striatum and improved gait dysfunction after MPTP administration. The neuroprotective effect of TFP5/TP5 peptide is also associated with marked reduction in neuroinflammation and apoptosis. Here we show selective inhibition of Cdk5/p25 hyperactivation by TFP5/TP5 peptide, which identifies the kinase as a potential therapeutic target to reduce neurodegeneration in Parkinson's disease.

引用

页码：4478 / 4491

页数：14

共 67 条

[1] Hyperphosphorylated tan and neurofilament and cytoskeletal disruptions in mice overexpressing human p25, an activator of cdk5 [J].