(b) 14-3-3 proteins interact with phosphorylated tyrosine hydroxylase (TH) to enhance its activity. 6-Mercaptopurine Monohydrate evidence 6-Mercaptopurine Monohydrate that 14-3-3 proteins regulate aspects of neurodegenerative disease with a focus on their protective functions against neurodegeneration. == 1. Introduction == 14-3-3 proteins were originally discovered as abundant molecules in the brain [1] and follow-up studies confirmed that the highest tissue concentration of 14-3-3 proteins is in the brain [2]. In fact, 14-3-3 proteins comprise about 1% of total protein from the brain. The role of 14-3-3 proteins has been widely studied because of their amazing capacity to impact the activity and localization of substrate proteins. In neurons, 14-3-3 proteins function in diverse processes including differentiation, migration, survival, neurite outgrowth, and ion channel regulation [3]. While their neurophysiological functions are not fully comprehended, 14-3-3 proteins have been implicated in a number of neurological disorders. In this review, we will discuss the evidence that 14-3-3 proteins have a neuroprotective role in the context of neurodegenerative disease. == 2. General Properties of 14-3-3 Proteins == The 14-3-3 family of adaptor proteins consists of seven isoforms in mammals (,,,,,, and/) [4]. The family was originally recognized and named during a systematic biochemical classification of brain PIK3CD proteins based on their elution number from biochemical fractionation columns [1]. Each family member forms a homo- or heterodimer and binds to target substrates most commonly through phospho-serine/threonine motifs [5,6]. Dimeric 14-3-3 proteins can bind to two different regions of the same protein to impact the conformation and activity of the substrate [79]. A specific protein conformation can be stabilized through 14-3-3 binding or specific phosphorylation sites can be guarded through 14-3-3 binding [9]. In addition, 14-3-3 dimers can bind to two different target proteins bringing them into close proximity, leading to a formation of a stable ternary complex [9]. In this way, 14-3-3s are capable of regulating the efficiency of enzymatic activity [1012]. Further, 14-3-3 proteins regulate the subcellular localization of their substrates to enhance a particular transmission or sequester and inhibit a particular pathway [13,14]. Thus, major molecular functions of 14-3-3 proteins could be summarized as follows: stabilizing specific conformations or modifications, regulating enzyme activity, and regulating subcellular localization. The occurrence of heterodimers confers an even higher diversity of 14-3-3 functions. The significance of the different isoforms is still not completely comprehended; however, functions and properties of some isoforms can be proposed. First, specific 14-3-3 isoforms are found in certain diseases. For instance,andisoform are absent in amyloid plaques in Alzheimer disease, while other isoforms are detected [15]. Second, some 14-3-3 interacting partners bind to 14-3-3 isoforms with significantly different affinities (e.g., c-Raf preferentially binds to 14-3-3isoforms [10]). In many cases, the dimerization of 14-3-3 proteins is crucial to their functions as adaptor proteins. However, the role of monomeric 14-3-3 proteins is also an emerging area of interest, particularly when considering the development of therapeutic brokers, which may target monomeric 14-3-3 proteins [16]. The presence of 14-3-3 monomers and dimers throughout the cytoplasm, at the plasma membrane, and within intracellular organelles makes this protein family a powerful molecular tool for 6-Mercaptopurine Monohydrate spatially regulating cell signaling [1721]. 14-3-3 proteins bind to substrate proteins through phosphodependent and phosphoindependent interactions [22,23]. To date more than 200 proteins have been found to interact with 14-3-3 family members, 6-Mercaptopurine Monohydrate including protein kinases, receptors, enzymes, structural and cytoskeletal proteins, small G-proteins and their regulators, scaffolding molecules, proteins involved in cell cycle control, proteins involved in transcriptional control of gene expression, and proteins involved in control of apoptosis [9,24,25]. This variety of interacting partner underlies the ability of 14-3-3 proteins to participate in such a wide array of cellular and physiological processes. == 3. 14-3-3 Proteins in Neurological Disorders == 14-3-3 proteins play diverse physiological functions and interact with a multitude of substrate proteins during normal development and adulthood [25,26]. Furthermore, many lines of evidence have recognized 14-3-3 proteins as important targets in neuropathological processes [27,28]. 14-3-3 proteins are detected in the cerebrospinal fluid in various neurodegenerative diseases, such as multiple sclerosis [2,29], Creutzfeldt-Jakob disease [3032], and HIV-related neurodegeneration [33]. 14-3-3 proteins also serve as a biomarker of neurological disorders characterized by extensive destruction of neurons in the brain including acute stroke [34] and subarachnoidal hemorrhage [35]. Together, these findings suggest that the presence of 14-3-3 proteins in the cerebrospinal fluid may be indicative of the destruction of brain tissue and leakage of normal cellular proteins into the cerebrospinal fluid. For this reason, 14-3-3 proteins are analyzed as potential biomarkers of neurodegeneration [36,37]. In addition, 14-3-3 proteins are found in disease-specific lesions and protein aggregates within the brain, and numerous studies have explained 14-3-3 interactions with target proteins that regulate pathogenic processes [3,27,28]. This supports the notion that 14-3-3 proteins are involved in the pathogenesis of neurodegenerative disease in addition to their power as general markers of tissue destruction. Because 14-3-3.