Focusing on cyclin-dependent kinases 5: A potential target for neurological disorders

Abstract

Cyclin-dependent kinases 5 (Cdk5) is a special member of proline-directed serine threonine kinase family. Unlike other Cdks, Cdk5 is not directly involved in cell cycle regulation but plays important roles in nervous system functions. Under physiological conditions, the activity of Cdk5 is tightly controlled by p35 or p39, which are specific activators of Cdk5 and highly expressed in post-mitotic neurons. However, they will be cleaved into the corresponding truncated forms namely p25 and p29 under pathological conditions, such as neurodegenerative diseases and neurotoxic insults. The binding to truncated co-activators results in aberrant Cdk5 activity and contributes to the initiation and progression of multiple neurological disorders through affecting the down-stream targets. Although Cdk5 kinase activity is mainly regulated through combining with co-activators, it is not the only way. Post-translational modifications of Cdk5 including phosphorylation, S-nitrosylation, sumoylation, and acetylation can also affect its kinase activity and then participate in physiological and pathological processes of nervous system. In this review, we focus on the regulatory mechanisms of Cdk5 and its roles in a series of common neurological disorders such as neurodegenerative diseases, stroke, anxiety/depression, pathological pain and epilepsy.

Cdk5 Sebagai Target Potensial Penemuan Obat Anti Nyeri Kronik

“…Strategi terapi genetik menggunakan siRNA dan shRNA untuk menghambat ekspresi dan fungsi dari Cdk5 saat ini masih dalam tahap penelitian, tidak hanya dalam bidang nyeri/neurologi namun juga pada penyakit ginjal dan terapi kanker. Tantangan terbesar dalam penggunaan terapi genetic adalah pemilihan vector untuk membawa RNA interference menuju sel target yang spesifik (Chiker et al, 2015;Tian et al, 2022;Zheng et al, 2016).…”

Cyclin‐dependent kinase 5 (CDK5) inhibitors in Parkinson disease

“…p25, the C‐terminal Cdk5 activation domain of p35, is generated by calpain cleavage. 21 The cleavage of p35 to p25 accompanies the activation of the kinase activity of Cdk5 and results in hyperactivation or abnormal activation. Hyperactivation of Cdk5 as in Alzheimer's disease (AD), is regulated by hyper‐phosphorylation of Cdk5‐specific phosphorylation sites such as Ser522 in collapsing response mediator protein‐2.…”

“…p35 is the major physiological Cdk5 activator, and the Cdk5‐p35 complex has moderate kinase activity in healthy neurons. p25, the C‐terminal Cdk5 activation domain of p35, is generated by calpain cleavage 21 . The cleavage of p35 to p25 accompanies the activation of the kinase activity of Cdk5 and results in hyperactivation or abnormal activation.…”