MAP/ERK Signaling in Developing Cognitive and Emotional Function and Its Effect on Pathological and Neurodegenerative Processes

The signaling pathway of the microtubule-associated protein kinase or extracellular regulated kinase (MAPK/ERK) is a common mechanism of extracellular information transduction from extracellular stimuli to the intracellular space. The transduction of information leads to changes in the ongoing metabolic pathways and the modification of gene expression patterns. In the central nervous system, ERK is expressed ubiquitously, both temporally and spatially. As for the temporal ubiquity, this signaling system participates in three key moments: (i) Embryonic development; (ii) the early postnatal period; and iii) adulthood. During embryonic development, the system is partly responsible for the patterning of segmentation in the encephalic vesicle through the FGF8-ERK pathway. In addition, during this period, ERK directs neurogenesis migration and the final fate of neural progenitors. During the early postnatal period, ERK participates in the maturation process of dendritic trees and synaptogenesis. During adulthood, ERK participates in social and emotional behavior and memory processes, including long-term potentiation. Alterations in mechanisms related to ERK are associated with different pathological outcomes. Genetic alterations in any component of the ERK pathway result in pathologies associated with neural crest derivatives and mental dysfunctions associated with autism spectrum disorders. The MAP-ERK pathway is a key element of the neuroinflammatory pathway triggered by glial cells during the development of neurodegenerative diseases, such as Parkinson’s and Alzheimer’s disease, Huntington’s disease, and amyotrophic lateral sclerosis, as well as prionic diseases. The process triggered by MAPK/ERK activation depends on the stage of development (mature or senescence), the type of cellular element in which the pathway is activated, and the anatomic neural structure. However, extensive gaps exist with regards to the targets of the phosphorylated ERK in many of these processes.

Download Full-text

MAPK/ERK Dysfunction in Neurodegenerative Diseases

10.32545/encyclopedia202007.0001.v3 ◽

2020 ◽

Author(s):

Hector Albert Gasco ◽

FRANCISCO ROS-BERNAL ◽

ESTHER CASTILLO-GÓMEZ ◽

Francisco Olucha-Bordonau

Keyword(s):

Neurodegenerative Diseases ◽

Expression Patterns ◽

Common Mechanism ◽

Neural Structure ◽

Cellular Element ◽

Intracellular Space ◽

Stage Of Development ◽

Extracellular Stimuli ◽

The Central Nervous System ◽

Extracellular Regulated Kinase

Download Full-text

Autism-associated variants of neuroligin 4X impair synaptogenic activity by various molecular mechanisms

10.21203/rs.2.19938/v2 ◽

2020 ◽

Author(s):

Takafumi Yumoto ◽

Misaki Kimura ◽

Ryota Nagatomo ◽

Tsukika Sato ◽

Shun Utsunomiya ◽

...

Keyword(s):

Cell Surface ◽

Psychiatric Disorders ◽

Molecular Mechanisms ◽

Genetic Alterations ◽

Autism Spectrum ◽

Copy Number Variations ◽

Proteolytic Processing ◽

Synaptic Activity ◽

Common Mechanism ◽

Dependent Manner

Abstract Background: Several genetic alterations, including point mutations and copy number variations in NLGN genes have been associated with psychiatric disorders, such as autism spectrum disorder (ASD) and X-linked mental retardation (XLMR). NLGN genes encode neuroligin (NL) proteins, which are adhesion molecules that are important for proper synaptic formation and maturation. Previously, we and others found that the expression level of murine NL1 is regulated by proteolytic processing in a synaptic activity-dependent manner. Methods: In this study, we analyzed the effects of missense variants associated with ASD and XLMR on the metabolism and function of NL4X, a protein which is encoded by the NLGN4X gene and is expressed only in humans, using cultured cells, primary neurons from rodents and human induced pluripotent stem cell-derived neurons. Results: NL4X was found to undergo proteolytic processing in human neuronal cells. Almost all NL4X variants caused a substantial decrease in the levels of mature NL4X and its synaptogenic activity in a heterologous culture system. Intriguingly, the L593F variant of NL4X accelerated the proteolysis of mature NL4X proteins located on the cell surface. In contrast, other variants decreased the cell-surface trafficking of NL4X. Notably, protease inhibitors as well as chemical chaperones rescued the expression of mature NL4X. Limitations: Our study did not reveal whether these dysfunctional phenotypes occurred in individuals carrying NLGN4X variant. Moreover, though these pathological mechanisms could be exploited as potential drug targets for ASD, it remains unclear whether these compounds would have beneficial effects on in ASD model animals and patients. Conclusions: These data suggest that reduced amounts of the functional NL4X protein on the cell surface is a common mechanism by which point mutants of the NL4X protein cause psychiatric disorders, although different molecular mechanisms are thought to be involved. Furthermore, these results highlight that the precision medicine approach based on genetic and cell biological analyses is important for the development of therapeutics for psychiatric disorders.

Download Full-text

Autism-associated variants of neuroligin 4X impair synaptogenic activity by various molecular mechanisms

10.21203/rs.2.19938/v1 ◽

2020 ◽

Author(s):

Takafumi Yumoto ◽

Misaki Kimura ◽

Ryota Nagatomo ◽

Hirotaka Watanabe ◽

Hideyuki Okano ◽

...

Keyword(s):

Cell Surface ◽

Psychiatric Disorders ◽

Molecular Mechanisms ◽

Genetic Alterations ◽

Autism Spectrum ◽

Copy Number Variations ◽

Proteolytic Processing ◽

Synaptic Activity ◽

Common Mechanism ◽

Dependent Manner

Abstract Several genetic alterations, including point mutations and copy number variations in NLGN genes have been associated with psychiatric disorders, such as autism spectrum disorder (ASD) and X-linked mental retardation (XLMR). NLGN genes encode neuroligin (NL) proteins, which are adhesion molecules that are important for proper synaptic formation and maturation. Previously, we and others found that the expression level of murine NL1 is regulated by proteolytic processing in a synaptic activity-dependent manner. In this study, we analyzed the effects of missense variants associated with ASD and XLMR on the metabolism and function of NL4X, a protein which is encoded by the NLGN4X gene and is expressed only in humans. NL4X was found to undergo proteolytic processing in human neuronal cells. Almost all NL4X variants caused a substantial decrease in the levels of mature NL4X and its synaptogenic activity in a heterologous culture system. Intriguingly, the L593F variant of NL4X accelerated the proteolysis of mature NL4X proteins located on the cell surface. In contrast, other variants decreased the cell-surface trafficking of NL4X. Notably, protease inhibitors as well as chemical chaperones rescued the expression of mature NL4X. These data suggest that reduced amounts of the functional NL4X protein on the cell surface is a common mechanism by which point mutants of the NL4X protein cause psychiatric disorders, although different molecular mechanisms are thought to be involved. Furthermore, these results highlight that the precision medicine approach based on genetic and cell biological analyses is important for the development of therapeutics for psychiatric disorders.

Download Full-text