JNK Pathway in CNS Pathologies

Abstract

The c-Jun N-terminal kinase (JNK) signalling pathway is a conserved response to a wide range of internal and external cellular stress signals. Beside the stress response, the JNK pathway is involved in a series of vital regulatory mechanisms during development and adulthood that are critical to maintain tissue homeostasis. These mechanisms include the regulation of apoptosis, growth, proliferation, differentiation, migration and invasion. The JNK pathway has a diverse functionality and cell-tissue specificity, and has emerged as a key player in regeneration, tumorigenesis and other pathologies. The JNK pathway is highly active in the central nervous system (CNS), and plays a central role when cells need to cope with pathophysiological insults during development and adulthood. Here, we review the implications of the JNK pathway in pathologies of the CNS. More specifically, we discuss some newly identified examples and mechanisms of JNK-driven tumor progression in glioblastoma, regeneration/repair after an injury, neurodegeneration and neuronal cell death. All these new discoveries support the central role of JNK in CNS pathologies and reinforce the idea of JNK as potential target to reduce their detrimental effects.

Suppression of LPS-Induced Inflammation and Cell Migration by Azelastine through Inhibition of JNK/NF-κB Pathway in BV2 Microglial Cells

“…The JNKs, depending on cellular alterations, are involved in the regulatory mechanisms of many physiological processes such as brain development, repair, and memory function. In addition, JNKs are also important modulators in inflammation and stress responses, which are critical features of the etiology and progression of many neurodegenerative diseases such as AD, PD, and multiple sclerosis [32,39,40]. In particular, JNK3, one of the three highly homologous JNKs, is abundantly and almost exclusively expressed in the brain and functions as an essential player of the neuronal immune response in various neuropathological conditions [13,41].…”

Dissection of the Regulatory Elements of the Complex Expression Pattern of Puckered, a Dual-Specificity JNK Phosphatase

“…puc expression has been reported in: (1) a population of lateral cells (LE cells) that delineates the boundary between the ectoderm and the amnioserosa during dorsal closure [21]; (2) the amnioserosa itself (transiently) [27]; (3) the peripheral embryonic nervous system [21,28]; (4) discrete neurons and neuronal precursors in the embryonic central nervous system (CNS) [26]; (5) epidermis and spiracles in the third instar larva [21]; (6) specific cell populations in all thoracic imaginal discs (the proximal part of the wing, haltere and leg discs, in the stalk, where imaginal discs connect to the larval epidermis and in the peripodial epithelium) [6,24]. Later during prepupariation, puc expression is maintained in the peripodial membrane and marks the presumptive suture sites of imaginal discs with their neighbors [29]; (7) all photoreceptor precursors (very weak) [30,31]; (8) sensory organs precursors in the wing, leg and haltere imaginal discs (weak) [32]; (9) larval muscles (very strong expression) [22]; (10) different types of follicular cells and the border cells in egg chambers [7,25]; (11) embryonic and larval hemocytes [33]; (12) induced at the edge of wounds in epithelial cells in embryos, larval epidermis and imaginal discs [34,35]; (13) epithelial regions surrounding necrotic areas [36]; (14) larval midgut [37]; and the adult brain [38].…”

“…During development, signaling mechanisms regulated by JNK have been shown to modulate epithelial fusion [6] and the cohesion of border cell clusters during migration [7] in Drosophila, as well as multiple morphogenetic processes and wound healing in vertebrates [8,9]. It has also a role in many different pathological conditions, such as atherosclerosis, Parkinson's or Alzheimer's disease [10,11].…”

JNK Signaling in Drosophila Aging and Longevity

“…For instance, in mouse models of Alzheimer's disease (AD), the most frequent neurodegenerative disorder, JNK3 phosphorylation levels correlate with the progression of AD, thus, it serves as a biomarker for AD. Mechanically, JNK3 phosphorylates the amyloid precursor protein (APP), causing amyloidogenic proteolytic processing and Aβ production in the brain [92]. In mouse models of Parkinson's disease (PD), another common neurodegenerative disease, JNK is involved in the activation of neuronal cell apoptosis through suppressing the function of antiapoptotic factor Bcl-2 [92].…”

“…Mechanically, JNK3 phosphorylates the amyloid precursor protein (APP), causing amyloidogenic proteolytic processing and Aβ production in the brain [92]. In mouse models of Parkinson's disease (PD), another common neurodegenerative disease, JNK is involved in the activation of neuronal cell apoptosis through suppressing the function of antiapoptotic factor Bcl-2 [92]. Thus, inhibition of the JNK signaling is considered to be a protective strategy against the neurodegeneration in AD and PD, and the JNK inhibitor has been proposed as the therapeutic candidate for these diseases [92].…”