JNK3 as Therapeutic Target and Biomarker in Neurodegenerative and Neurodevelopmental Brain Diseases

Musi, Clara Alice; Agrò, Graziella; Santarella, Francesco; Iervasi, Erika; Borsello, Tiziana

doi:10.3390/cells9102190

Cited by 48 publications

(47 citation statements)

References 154 publications

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“…MAPK10 (FC = 1.09, p = 0.05) encodes mitogen-activated protein kinase 10, which is a neuron-specific map kinase enzyme in the JNK signalling pathway. MAPK10 has been identified as a possible target and biomarker of neurodegenerative diseases [ 104 ]. Indeed, MAPK10 is associated with processes of ageing and neurological deficits [ 168 ] and enhances both amyloid beta production through the phosphorylation of amyloid precursor protein (APP) [ 74 ] and the maturation and development of neurofibrillary tangles [ 170 ].…”

Section: Resultsmentioning

confidence: 99%

Early onset senescence and cognitive impairment in a murine model of repeated mTBI

Schwab

Hazrati

2021

acta neuropathol commun

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Mild traumatic brain injury (mTBI) results in broad neurological symptoms and an increased risk of being diagnosed with a neurodegenerative disease later in life. While the immediate oxidative stress response and post-mortem pathology of the injured brain has been well studied, it remains unclear how early pathogenic changes may drive persistent symptoms and confer susceptibility to neurodegeneration. In this study we have used a mouse model of repeated mTBI (rmTBI) to identify early gene expression changes at 24 h or 7 days post-injury (7 dpi). At 24 h post-injury, gene expression of rmTBI mice shows activation of the DNA damage response (DDR) towards double strand DNA breaks, altered calcium and cell–cell signalling, and inhibition of cell death pathways. By 7 dpi, rmTBI mice had a gene expression signature consistent with induction of cellular senescence, activation of neurodegenerative processes, and inhibition of the DDR. At both timepoints gliosis, microgliosis, and axonal damage were evident in the absence of any gross lesion, and by 7 dpi rmTBI also mice had elevated levels of IL1β, p21, 53BP1, DNA2, and p53, supportive of DNA damage-induced cellular senescence. These gene expression changes reflect establishment of processes usually linked to brain aging and suggests that cellular senescence occurs early and most likely prior to the accumulation of toxic proteins. These molecular changes were accompanied by spatial learning and memory deficits in the Morris water maze. To conclude, we have identified DNA damage-induced cellular senescence as a repercussion of repeated mild traumatic brain injury which correlates with cognitive impairment. Pathways involved in senescence may represent viable treatment targets of post-concussive syndrome. Senescence has been proposed to promote neurodegeneration and appears as an effective target to prevent long-term complications of mTBI, such as chronic traumatic encephalopathy and other related neurodegenerative pathologies.

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Section: Resultsmentioning

confidence: 99%

Early onset senescence and cognitive impairment in a murine model of repeated mTBI

Schwab

Hazrati

2021

acta neuropathol commun

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“…Aging, accumulation of misfolded proteins, oxidative stress, inflammation and hypoxia are the classical stimuli that alter cell homeostasis and shift the balance into a stressful condition, in which cells tend to degenerate (reviewed in [ 51 , 52 ]). JNK3, the major isoform expressed in the CNS, contributes to neuronal cell degeneration in this context (reviewed in [ 29 , 53 ]). JNK3 also plays a role in synapse dysfunction, one of the first events in neurodegenerative and neurodevelopmental brain diseases [ 54 ].…”

Section: Jnk In Neurodegenerative Disordersmentioning

confidence: 99%

“…In addition, the literature reveals a dual role of the JNK pathway in cell death and cell survival, depending on the cell type and the context [ 11 ]. This two-faded role is particularly important in CNS pathologies such as neurodegeneration and tumorigenesis, in which the cellular stress-associated signals are increased [ 29 , 30 ]. Likewise, JNK signalling is involved in neurogenesis, axonal growth, axonal transport, brain metabolism, animal behavior, neurulation, migration and axon–dendritic architecture in different species [ 21 , 22 , 23 , 31 , 32 ].…”

Section: Introductionmentioning

confidence: 99%

JNK Pathway in CNS Pathologies

Corrales

Losada‐Pérez

Casas‐Tintó

2021

IJMS

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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.

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Section: Introductionmentioning

confidence: 99%

“…JNK belongs to the family of MAPKs and encompasses three encoded genes, JNK1, JNK2 and JNK3 ( 1 ). JNK1 and JNK2 are widely expressed in various tissues, whereas JNK3 is primarily expressed in the brain and heart ( 1 , 2 ). JNK is also known as stress-activated kinase, which is involved in the regulation of the response of the body to external or internal stimuli, inflammation and cell apoptosis ( 3 ).…”

Section: Introductionmentioning

confidence: 99%

Selective inhibition of JNK mitochondrial location is protective against seawater inhalation‑induced ALI/ARDS

Liu

et al. 2021

Mol Med Rep

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Localization of phosphorylated (p)-JNK to the mitochondria can lead to functional mitochondrial disorder, resulting in a decrease in energy supply and membrane potential, as well as an increase in reactive oxygen species production and apoptosis. JNK is involved in the occurrence of acute lung injury (ALI), and activation of the JNK pathway is one of the crucial factors resulting in injury. The aim of the present study was to investigate whether the JNK-mitochondria (mitoJNK) location participated in the occurrence of ALI and acute respiratory distress syndrome (ALI/ARDS). The present study examined the activation of the JNK pathway, the content of JNK located on the mitochondria and the treatment effects of a cell-permeable peptide Tat-Sab KIM1 , which can selectively inhibit the location of JNK on mitochondria. The expression levels of proteins were detected by western blot analysis. Lung injuries were evaluated by histological examination, wet-to-dry weight ratios, and H 2 O 2 and malondialdehyde concentrations in the lung tissues. Lung cells apoptosis was evaluated using TUNEL assay. The results demonstrated that JNK was phosphorylated and activated during seawater inhalation-induced ALI/ARDS, not only in the routine JNK pathway but also in the mitoJNK pathway. It was also found that Tat-Sab KIM1 could specifically inhibit JNK localization to mitochondria and the activation of mitoJNK signaling. Furthermore, Tat-Sab KIM1 could inhibit Bcl-2-regulated autophagy and mitochondria-mediated apoptosis. In conclusion, mitoJNK localization disrupted the normal physiological functions of the mitochondria during ALI/ARDS, and selective inhibition of JNK and mitochondrial SH3BP5 (also known as Sab) binding with Tat-Sab KIM1 can block deterioration from ALI/ARDS.

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JNK3 as Therapeutic Target and Biomarker in Neurodegenerative and Neurodevelopmental Brain Diseases

Cited by 48 publications

References 154 publications

Early onset senescence and cognitive impairment in a murine model of repeated mTBI

Early onset senescence and cognitive impairment in a murine model of repeated mTBI

JNK Pathway in CNS Pathologies

Selective inhibition of JNK mitochondrial location is protective against seawater inhalation‑induced ALI/ARDS

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