MAPK/ERK Dysfunction in Neurodegenerative Diseases Abstract MAPK signaling pathways intervene and control cellular functions, resulting in a direct function of memory and emotional processes. Therefore, alterations or modulations of these pathways can lead to different processes implicated in various human diseases. Throughout this and the next section, we will analyze the state-of-the-art of MAPK signaling pathways in human disease, with a special focus on neurodegenerative disorders (Table 1). The role of the MAPK/ERK pathway in neurodegenerative diseases is mainly related to glial cell function and the inflammatory response. The activation of resident immune cells of the brain, glial cells (microglia and astroglia), triggers the pro-inflammatory state with the production of nitric oxide (NO), cytokines, and chemokines and the implication of inflammatory-related pathways . Most of the components of these pathways are cytosolic targets of ERK, suggesting an essential function of the MAPK pathway in the production or sustaining of such a pathological hallmark, and consequently, in the noxious events that lead to the specific neurodegeneration. Parkinson´s Disease Parkinson's disease (PD) is an age-associated disease mostly identified by an extrapyramidal alteration of movement. From a pathological point of view, PD is characterized by the selective and progressive loss of dopaminergic- melanized neurons located in caudoventral regions of the substantia nigra, reactive gliosis, and intracytoplasmic inclusions of a-synuclein known as the Lewy bodies . In this sense, α-Synuclein promotes inflammation via activating p38, ERK, and JNK pathways in human microglial cells, resulting in the production of IL-1β and TNF-α. The disappearance of neurons in the substantia nigra leads to dopamine deficiency in their target areas (in the striatum Contributors: , Hector Albert Gasco , Francisco Ros-bernal , Esther Castillo-gÓmez , Francisco Olucha-bordonau 1, UK Dementia Research Institute at the University of Cambridge and Department of Clinical Neurosciences, University of Cambridge, Cambridge; ha437@medschl.cam.ac.uk 2, UP Medicine, School of Health Sciences, Universitat Jaume I, Castellón de la Plana, Spain ; fros@uji.es 3, UP Medicine, School of Health Sciences, Universitat Jaume I, Castellón de la Plana, Spain Spanish National Network for Research in Mental Health, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain; escastil@uji.es 4, UP Medicine, School of Health Sciences, Universitat Jaume I, Castellón de la Plana, Spain ; folucha@uji.es Version received: 2 July 2020 1 2 3 4 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. 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. Table of Contents [Hide] [1 ][2 ][3 ] [4 ] Encyclopedia 2020 doi: 10.32545/encyclopedia202007.0001.v3 1