PAK in Alzheimer disease, Huntington disease and X-linked mental retardation

Abstract

Developmental cognitive deficits including X-linked mental retardation (XLMR) can be caused by mutations in P21-activated kinase 3 (PAK3) that disrupt actin dynamics in dendritic spines. Neurodegenerative diseases such as Alzheimer disease (AD), where both PAK1 and PAK3 are dysregulated, may share final common pathways with XLMR. Independent of familial mutation, cognitive deficits emerging with aging, notably AD, begin after decades of normal function. This prolonged prodromal period involves the buildup of amyloid-β (Aβ) extracellular plaques and intraneuronal neurofibrillary tangles (NFT). Subsequently region dependent deficits in synapses, dendritic spines and cognition coincide with dysregulation in PAK1 and PAK. Specifically proximal to decline, cytoplasmic levels of actin-regulating Rho GTPase and PAK1 kinase are decreased in moderate to severe AD, while aberrant activation and translocation of PAK1 appears around the onset of cognitive deficits. Downstream to PAK1, LIM kinase inactivates cofilin, contributing to cofilin pathology, while the activation of Rho-dependent kinase ROCK increases Aβ production. Aβ activation of fyn disrupts neuronal PAK1 and ROCK-mediated signaling, resulting in synaptic deficits. Reductions in PAK1 by the anti-amyloid compound curcumin suppress synaptotoxicity. Similarly other neurological disorders, including Huntington disease (HD) show dysregulation of PAKs. PAK1 modulates mutant huntingtin toxicity by enhancing huntingtin aggregation, and inhibition of PAK activity protects HD as well as fragile X syndrome (FXS) symptoms. Since PAK plays critical roles in learning and memory and is disrupted in many cognitive disorders, targeting PAK signaling in AD, HD and XLMR may be a novel common therapeutic target for AD, HD and XLMR.

The associated pyrazolopyrimidines PP1 and PP2 inhibit protein tyrosine kinase 6 activity and suppress breast cancer cell proliferation

“…Although PP1 and PP2 are more selective for SFKs than the previous generation of PTK inhibitors (including herbimycin A and genistein), they can inhibit off-target kinases (including C-terminal Src kinase, ephrin type-A receptor 2, platelet-derived growth factor receptor, fibroblast growth factor receptor 1, p21 activated kinase, receptor-interacting protein 2, p38 and casein kinase 1δ) with sufficient potency (24)(25)(26)(27). When the selectivity of these chemicals for various PTKs was analyzed in HEK 293 cells expressing one of the PTKs, they displayed high selectivity for PTK6 over various SFK members, including Src, Fyn, Lck, and other PTK family members such as Bmx and EGFR.…”

BRAF activates and physically interacts with PAK to regulate cell motility

“…PAKs play important roles in breast cancer development and progression (Rider, et al 2013; Shrestha, et al 2012), in schwannoma development as effectors of NF2 (Flaiz, et al 2009), and in neurological syndromes (Ma QL 2012). The six isoforms of PAK are divided into group I (PAKs 1-3) and group II (PAKs 4-6) based on structural and functional similarities (Radu M 2014).…”

Short case report: Xq23 deletion involving PAK3 as a novel cause of developmental delay in a 6-year-old boy

“…The PAK3 protein functions in regulating the actin cytoskeleton of cells and is also involved in neuronal stimulation and outgrowth in the foetal and adult brain (Ma et al, 2012). Nonsense, missense and splice site mutations within the PAK3 gene have all been previously associated with nonsyndromic X-linked mental retardation (Donnelly et al, 1996;des Portes et al, 1997;Allen et al, 1998;Bienvenu et al, 2000;Gedeon et al, 2003; …”