RESUMO
C-Jun-N-terminal-kinases (JNKs), members of the mitogen-activated-protein-kinase family, are significantly linked with neurological and neurodegenerative pathologies and cancer progression. However, JNKs serve key roles under physiological conditions, particularly within the central-nervous-system (CNS), where they are critical in governing neural proliferation and differentiation during both embryogenesis and adult stages. These processes control the development of CNS, avoiding neurodevelopment disorders. JNK are key to maintain the proper activity of neural-stem-cells (NSC) and neural-progenitors (NPC) that exist in adults, which keep the convenient brain plasticity and homeostasis. This review underscores how the interaction of JNK with upstream and downstream molecules acts as a regulatory mechanism to manage the self-renewal capacity and differentiation of NSC/NPC during CNS development and in adult neurogenic niches. Evidence suggests that JNK is reliant on non-canonical Wnt components, Fbw7-ubiquitin-ligase, and WDR62-scaffold-protein, regulating substrates such as transcription factors and cytoskeletal proteins. Therefore, understanding which pathways and molecules interact with JNK will bring knowledge on how JNK activation orchestrates neuronal processes that occur in CNS development and brain disorders.
Assuntos
Diferenciação Celular , Células-Tronco Neurais , Neurogênese , Humanos , Animais , Diferenciação Celular/fisiologia , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/citologia , Neurogênese/fisiologia , Sistema de Sinalização das MAP Quinases/fisiologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Neurônios/metabolismo , Neurônios/citologiaRESUMO
Protein tyrosine phosphatase 1B (PTP1B) is a typical member of the PTP family, considered a direct negative regulator of several receptor and receptor-associated tyrosine kinases. This widely localized enzyme has been involved in the pathophysiology of several diseases. More recently, PTP1B has attracted attention in the field of neuroscience, since its activation in brain cells can lead to schizophrenia-like behaviour deficits, anxiety-like effects, neurodegeneration, neuroinflammation and depression. Conversely, PTP1B inhibition has been shown to prevent microglial activation, thus exerting a potent anti-inflammatory effect and has also shown potential to increase the cognitive process through the stimulation of hippocampal insulin, leptin and BDNF/TrkB receptors. Notwithstanding, most research on the clinical efficacy of targeting PTP1B has been developed in the field of obesity and type 2 diabetes mellitus (TD2M). However, despite the link existing between these metabolic alterations and neurodegeneration, no clinical trials assessing the neurological advantages of PTP1B inhibition have been performed yet. Preclinical studies, though, have provided strong evidence that targeting PTP1B could allow to reach different pathophysiological mechanisms at once. herefore, specific interventions or trials should be designed to modulate PTP1B activity in brain, since it is a promising strategy to decelerate or prevent neurodegeneration in aged individuals, among other neurological diseases. The present paper fails to include all neurological conditions in which PTP1B could have a role; instead, it focuses on those which have been related to metabolic alterations and neurodegenerative processes. Moreover, only preclinical data is discussed, since clinical studies on the potential of PTP1B inhibition for treating neurological diseases are still required.
Assuntos
Diabetes Mellitus Tipo 2 , Doenças do Sistema Nervoso , Humanos , Idoso , Proteína Tirosina Fosfatase não Receptora Tipo 1 , Leptina , Diabetes Mellitus Tipo 2/tratamento farmacológico , Fator Neurotrófico Derivado do Encéfalo , Insulina/uso terapêutico , Doenças do Sistema Nervoso/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Tirosina , Inibidores Enzimáticos/farmacologiaRESUMO
The c-Jun N-terminal Kinases (JNKs) are a group of regulatory elements responsible for the control of a wide array of functions within the cell. In the central nervous system (CNS), JNKs are involved in neuronal polarization, starting from the cell division of neural stem cells and ending with their final positioning when migrating and maturing. This review will focus mostly on isoform JNK1, the foremost contributor of total JNK activity in the CNS. Throughout the text, research from multiple groups will be summarized and discussed in order to describe the involvement of the JNKs in the different steps of neuronal polarization. The data presented support the idea that isoform JNK1 is highly relevant to the regulation of many of the processes that occur in neuronal development in the CNS.
Assuntos
Encéfalo/citologia , Encéfalo/crescimento & desenvolvimento , Polaridade Celular/fisiologia , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Neurônios/metabolismo , Animais , Proteína Duplacortina , Humanos , Isoenzimas , Camundongos , Fosforilação/fisiologia , Transdução de Sinais/fisiologiaRESUMO
Neurological and psychiatric disorders are leading contributors to the global disease burden, having a serious impact on the quality of life of both patients and their relatives. Although the molecular events underlying these heterogeneous diseases remain poorly understood, some studies have raised the idea of common mechanisms involved. In excitotoxicity, there is an excessive activation of glutamate receptors by excitatory amino acids, leading to neuronal damage. Thus, the excessive release of glutamate can lead to a dysregulation of Ca2+ homeostasis, triggering the production of free radicals and oxidative stress, mitochondrial dysfunction and eventually cell death. Although there is a consensus in considering excitotoxicity as a hallmark in most neurodegenerative diseases, increasing evidence points to the relevant role of this pathological mechanism in other illnesses affecting the central nervous system. Consequently, antagonists of glutamate receptors are used in current treatments or in clinical trials in both neurological and psychiatric disorders. However, drugs modulating other aspects of the excitotoxic mechanism could be more beneficial. This review discusses how excitotoxicity is involved in the pathogenesis of different neurological and psychiatric disorders and the promising strategies targeting the excitotoxic insult.