Three decades of Cdk5

Abstract

Cdk5 is a proline-directed serine/threonine protein kinase that governs a variety of cellular processes in neurons, the dysregulation of which compromises normal brain function. The mechanisms underlying the modulation of Cdk5, its modes of action, and its effects on the nervous system have been a great focus in the field for nearly three decades. In this review, we provide an overview of the discovery and regulation of Cdk5, highlighting recent findings revealing its role in neuronal/synaptic functions, circadian clocks, DNA damage, cell cycle reentry, mitochondrial dysfunction, as well as its non-neuronal functions under physiological and pathological conditions. Moreover, we discuss evidence underscoring aberrant Cdk5 activity as a common theme observed in many neurodegenerative diseases.

Keywords: Alzheimer’s disease; Cdk5; Neurodegeneration; p25; p35.

Fig. 1

Single-cell transcriptomic analysis of the expression of Cdk5, Cdk5r1 (the gene encoding p35), and Cdk5r2 (the gene encoding p39) in young and aged mouse brain. The data are based on Ximerakis et al., 2019, Nat. Neurosci., and the graphs were generated by Single Cell Portal website (https://singlecell.broadinstitute.org/single_cell/study/SCP263/aging-mouse-brain). Astrocyte lineage: neural stem cells, astrocyte-restricted precursors and astrocytes. Ependymal cells: ependymocytes, hypendymal cells, tancytes, and choroid plexus epithelial cells. Immune cells: microglia, monocytes, macrophages, dendritic cells, and neutrophils. Neuronal lineage: neuronal-restricted precursors, immature neurons, mature neurons, and neuroendocrine cells. Vasculature cells: endothelial cells, pericytes, hemoglobin-expressing vascular cells, vascular smooth muscle cells, vascular and leptomeningeal cells, and arachnoid barrier cells

Fig. 2

Activation of Cdk5 and its functions under physiological or pathological conditions