The p21-activated kinases in neural cytoskeletal remodeling and related neurological disorders

Abstract

The serine/threonine p21-activated kinases (PAKs), as main effectors of the Rho GTPases Cdc42 and Rac, represent a group of important molecular switches linking the complex cytoskeletal networks to broad neural activity. PAKs show wide expression in the brain, but they differ in specific cell types, brain regions, and developmental stages. PAKs play an essential and differential role in controlling neural cytoskeletal remodeling and are related to the development and fate of neurons as well as the structural and functional plasticity of dendritic spines. PAK-mediated actin signaling and interacting functional networks represent a common pathway frequently affected in multiple neurodevelopmental and neurodegenerative disorders. Considering specific small-molecule agonists and inhibitors for PAKs have been developed in cancer treatment, comprehensive knowledge about the role of PAKs in neural cytoskeletal remodeling will promote our understanding of the complex mechanisms underlying neurological diseases, which may also represent potential therapeutic targets of these diseases.

Single-nucleus transcriptomic landscape of primate hippocampal aging

“…GRM8, downregulated in aged InN, encodes a glutamate metabotropic receptor of neurotransmitter L-glutamate, and is known to facilitate neuronal resilience to central nervous system (CNS) inflammation (Woo et al, 2021). PAK5 was downregulated in OL, which may impair cytoskeletal remodeling, and compromise the synaptic vesicle trafficking and axon-myelin contacts (Zhang et al, 2020a). These dysregulated genes may underlie the progressive functional decay of hippocampal cells during aging.…”

Neuronal Cytoskeleton in Intellectual Disability: From Systems Biology and Modeling to Therapeutic Opportunities

“…Based on their sequence homology, PAKs are classified into two groups, the first including PAK1, PAK2, and PAK3 and the second including PAK4, PAK5, and PAK6. All six PAKs are expressed in the nervous system with a different spatio-temporal pattern, with PAK1 and 3 being the most studied in the context of neuronal function [ 114 ]. Active RAC1 and CDC42 bind to the CRIB region of PAK1, relieving its autoinhibition and promoting its kinase activity [ 115 , 116 , 117 ].…”

Pak1 kinase controls cell shape through ribonucleoprotein granules

“…Following activation by small GTPases like Cdc42, PAKs function in regulating the cytoskeleton and MAPK pathways, and PAK dysregulation is associated with multiple human diseases. For example, PAKs regulate the elaborate architecture of highly polarized neurons, and PAK loss-of-function mutations impair neuronal migration, neurite outgrowth, and axonal development, leading to connections with autism spectrum disorders, Alzheimer's disease, neurofibromatosis type 1, and other neurological disorders (Zhang et al, 2020). Aberrant activation of human PAK1 also drives cell migration and proliferation in multiple forms of cancer including pancreatic, breast, prostate, and thyroid (Bautista et al, 2020;Kanumuri et al, 2020;Rane and Minden, 2019).…”