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The Peptide-Directed Lysosomal Degradation of CDK5 Exerts Therapeutic Effects against Stroke.

ABSTRACT: The aberrant activation of CDK5 has been implicated in neuronal death in stroke. The goal of this study is to determine whether knocking down CDK5 by a peptide-directed lysosomal degradation approach is therapeutically effective against stroke. We synthesized a membrane-permeable peptide that specifically binds to CDK5 with a chaperone-mediated autophagy targeting motif (Tat-CDK5-CTM) and tested its therapeutic effects on a mouse model of ischemic stroke. Our results showed that Tat-CDK5-CTM blocked the CDK5-NR2B interaction, resulting in the degradation of CDK5, which in turn prevented calcium overload and neuronal death in cultured neurons. Tat-CDK5-CTM also reduced the infarction area and neuronal loss and improved the neurological functions in MCAO (Middle cerebral artery occlusion) mice. The peptide-directed lysosomal degradation of CDK5 is a promising therapeutic intervention for stroke.

SUBMITTER: Zhou YF

PROVIDER: S-EPMC6764726 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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The Peptide-Directed Lysosomal Degradation of CDK5 Exerts Therapeutic Effects against Stroke.

Zhou Ya-Fan YF Wang Jing J Deng Man-Fei MF Chi Bin B Wei Na N Chen Jian-Guo JG Liu Dan D Yin Xiaoping X Lu Youming Y Zhu Ling-Qiang LQ

Aging and disease 20191001 5

The aberrant activation of CDK5 has been implicated in neuronal death in stroke. The goal of this study is to determine whether knocking down CDK5 by a peptide-directed lysosomal degradation approach is therapeutically effective against stroke. We synthesized a membrane-permeable peptide that specifically binds to CDK5 with a chaperone-mediated autophagy targeting motif (Tat-CDK5-CTM) and tested its therapeutic effects on a mouse model of ischemic stroke. Our results showed that Tat-CDK5-CTM blo ...[more]

PMID: 31595208

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