Neuroprotective Function of 14-3-3 Proteins in Neurodegeneration
Identifieur interne : 000931 ( Pmc/Corpus ); précédent : 000930; suivant : 000932Neuroprotective Function of 14-3-3 Proteins in Neurodegeneration
Auteurs : Tadayuki Shimada ; Alyson E. Fournier ; Kanato YamagataSource :
- BioMed Research International [ 2314-6133 ] ; 2013.
Abstract
14-3-3 proteins are abundantly expressed adaptor proteins that interact with a vast number of binding partners to regulate their cellular localization and function. They regulate substrate function in a number of ways including protection from dephosphorylation, regulation of enzyme activity, formation of ternary complexes and sequestration. The diversity of 14-3-3 interacting partners thus enables 14-3-3 proteins to impact a wide variety of cellular and physiological processes. 14-3-3 proteins are broadly expressed in the brain, and clinical and experimental studies have implicated 14-3-3 proteins in neurodegenerative disease. A recurring theme is that 14-3-3 proteins play important roles in pathogenesis through regulating the subcellular localization of target proteins. Here, we review the evidence that 14-3-3 proteins regulate aspects of neurodegenerative disease with a focus on their protective roles against neurodegeneration.
Url:
DOI: 10.1155/2013/564534
PubMed: 24364034
PubMed Central: 3865737
Links to Exploration step
PMC:3865737Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Neuroprotective Function of 14-3-3 Proteins in Neurodegeneration</title><author><name sortKey="Shimada, Tadayuki" sort="Shimada, Tadayuki" uniqKey="Shimada T" first="Tadayuki" last="Shimada">Tadayuki Shimada</name><affiliation><nlm:aff id="I1">Neural Plasticity Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan</nlm:aff></affiliation></author><author><name sortKey="Fournier, Alyson E" sort="Fournier, Alyson E" uniqKey="Fournier A" first="Alyson E." last="Fournier">Alyson E. Fournier</name><affiliation><nlm:aff id="I2">Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada H3A 2B4</nlm:aff></affiliation></author><author><name sortKey="Yamagata, Kanato" sort="Yamagata, Kanato" uniqKey="Yamagata K" first="Kanato" last="Yamagata">Kanato Yamagata</name><affiliation><nlm:aff id="I1">Neural Plasticity Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">24364034</idno><idno type="pmc">3865737</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3865737</idno><idno type="RBID">PMC:3865737</idno><idno type="doi">10.1155/2013/564534</idno><date when="2013">2013</date><idno type="wicri:Area/Pmc/Corpus">000931</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000931</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Neuroprotective Function of 14-3-3 Proteins in Neurodegeneration</title><author><name sortKey="Shimada, Tadayuki" sort="Shimada, Tadayuki" uniqKey="Shimada T" first="Tadayuki" last="Shimada">Tadayuki Shimada</name><affiliation><nlm:aff id="I1">Neural Plasticity Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan</nlm:aff></affiliation></author><author><name sortKey="Fournier, Alyson E" sort="Fournier, Alyson E" uniqKey="Fournier A" first="Alyson E." last="Fournier">Alyson E. Fournier</name><affiliation><nlm:aff id="I2">Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada H3A 2B4</nlm:aff></affiliation></author><author><name sortKey="Yamagata, Kanato" sort="Yamagata, Kanato" uniqKey="Yamagata K" first="Kanato" last="Yamagata">Kanato Yamagata</name><affiliation><nlm:aff id="I1">Neural Plasticity Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan</nlm:aff></affiliation></author></analytic><series><title level="j">BioMed Research International</title><idno type="ISSN">2314-6133</idno><idno type="eISSN">2314-6141</idno><imprint><date when="2013">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>14-3-3 proteins are abundantly expressed adaptor proteins that interact with a vast number of binding partners to regulate their cellular localization and function. They regulate substrate function in a number of ways including protection from dephosphorylation, regulation of enzyme activity, formation of ternary complexes and sequestration. The diversity of 14-3-3 interacting partners thus enables 14-3-3 proteins to impact a wide variety of cellular and physiological processes. 14-3-3 proteins are broadly expressed in the brain, and clinical and experimental studies have implicated 14-3-3 proteins in neurodegenerative disease. A recurring theme is that 14-3-3 proteins play important roles in pathogenesis through regulating the subcellular localization of target proteins. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Biomed Res Int</journal-id><journal-id journal-id-type="iso-abbrev">Biomed Res Int</journal-id><journal-id journal-id-type="publisher-id">BMRI</journal-id><journal-title-group><journal-title>BioMed Research International</journal-title></journal-title-group><issn pub-type="ppub">2314-6133</issn><issn pub-type="epub">2314-6141</issn><publisher><publisher-name>Hindawi Publishing Corporation</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">24364034</article-id><article-id pub-id-type="pmc">3865737</article-id><article-id pub-id-type="doi">10.1155/2013/564534</article-id><article-categories><subj-group subj-group-type="heading"><subject>Review Article</subject></subj-group></article-categories><title-group><article-title>Neuroprotective Function of 14-3-3 Proteins in Neurodegeneration</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Shimada</surname><given-names>Tadayuki</given-names></name><xref ref-type="aff" rid="I1"><sup>1</sup></xref><xref ref-type="corresp" rid="cor1">*</xref></contrib><contrib contrib-type="author"><name><surname>Fournier</surname><given-names>Alyson E.</given-names></name><xref ref-type="aff" rid="I2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Yamagata</surname><given-names>Kanato</given-names></name><xref ref-type="aff" rid="I1"><sup>1</sup></xref></contrib></contrib-group><aff id="I1"><sup>1</sup>Neural Plasticity Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan</aff><aff id="I2"><sup>2</sup>Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada H3A 2B4</aff><author-notes><corresp id="cor1">*Tadayuki Shimada: <email>shimada-td@igakuken.or.jp</email></corresp><fn fn-type="other"><p>Academic Editor: Anna Maria Lavezzi</p></fn></author-notes><pub-date pub-type="ppub"><year>2013</year></pub-date><pub-date pub-type="epub"><day>2</day><month>12</month><year>2013</year></pub-date><volume>2013</volume><elocation-id>564534</elocation-id><history><date date-type="received"><day>26</day><month>8</month><year>2013</year></date><date date-type="accepted"><day>17</day><month>10</month><year>2013</year></date></history><permissions><copyright-statement>Copyright © 2013 Tadayuki Shimada et al.</copyright-statement><copyright-year>2013</copyright-year><license xlink:href="https://creativecommons.org/licenses/by/3.0/"><license-p>This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</license-p></license></permissions><abstract><p>14-3-3 proteins are abundantly expressed adaptor proteins that interact with a vast number of binding partners to regulate their cellular localization and function. They regulate substrate function in a number of ways including protection from dephosphorylation, regulation of enzyme activity, formation of ternary complexes and sequestration. The diversity of 14-3-3 interacting partners thus enables 14-3-3 proteins to impact a wide variety of cellular and physiological processes. 14-3-3 proteins are broadly expressed in the brain, and clinical and experimental studies have implicated 14-3-3 proteins in neurodegenerative disease. A recurring theme is that 14-3-3 proteins play important roles in pathogenesis through regulating the subcellular localization of target proteins. Here, we review the evidence that 14-3-3 proteins regulate aspects of neurodegenerative disease with a focus on their protective roles against neurodegeneration.</p></abstract></article-meta></front><body><sec id="sec1"><title>1. Introduction</title><p>14-3-3 proteins were originally discovered as abundant molecules in the brain [<xref rid="B1" ref-type="bibr">1</xref>] and follow-up studies confirmed that the highest tissue concentration of 14-3-3 proteins is in the brain [<xref rid="B2" ref-type="bibr">2</xref>]. 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 remarkable capacity to affect 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 [<xref rid="B3" ref-type="bibr">3</xref>]. While their neurophysiological functions are not fully understood, 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.</p></sec><sec id="sec2"><title>2. General Properties of 14-3-3 Proteins</title><p>The 14-3-3 family of adaptor proteins consists of seven isoforms in mammals (<italic>β</italic>, <italic>γ</italic>, <italic>ε</italic>, <italic>η</italic>, <italic>ζ</italic>, <italic>σ</italic>, and <italic>τ</italic>/<italic>θ</italic>) [<xref rid="B4" ref-type="bibr">4</xref>]. The family was originally identified and named during a systematic biochemical classification of brain proteins based on their elution number from biochemical fractionation columns [<xref rid="B1" ref-type="bibr">1</xref>]. Each family member forms a homo- or heterodimer and binds to target substrates most commonly through phospho-serine/threonine motifs [<xref rid="B5" ref-type="bibr">5</xref>, <xref rid="B6" ref-type="bibr">6</xref>]. Dimeric 14-3-3 proteins can bind to two different regions of the same protein to affect the conformation and activity of the substrate [<xref rid="B7" ref-type="bibr">7</xref>–<xref rid="B9" ref-type="bibr">9</xref>]. A specific protein conformation can be stabilized through 14-3-3 binding or specific phosphorylation sites can be protected through 14-3-3 binding [<xref rid="B9" ref-type="bibr">9</xref>]. 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 [<xref rid="B9" ref-type="bibr">9</xref>]. In this way, 14-3-3s are capable of regulating the efficiency of enzymatic activity [<xref rid="B10" ref-type="bibr">10</xref>–<xref rid="B12" ref-type="bibr">12</xref>]. Further, 14-3-3 proteins regulate the subcellular localization of their substrates to enhance a particular signal or sequester and inhibit a particular pathway [<xref rid="B13" ref-type="bibr">13</xref>, <xref rid="B14" ref-type="bibr">14</xref>]. 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.</p><p>The occurrence of heterodimers confers an even higher diversity of 14-3-3 functions. The significance of the different isoforms is still not completely understood; however, functions and properties of some isoforms can be proposed. First, specific 14-3-3 isoforms are found in certain diseases. For instance, <italic>η</italic> and <italic>θ</italic> isoform are absent in amyloid plaques in Alzheimer disease, while other isoforms are detected [<xref rid="B15" ref-type="bibr">15</xref>]. Second, some 14-3-3 interacting partners bind to 14-3-3 isoforms with significantly different affinities (e.g., c-Raf preferentially binds to 14-3-3 <italic>η</italic> isoforms [<xref rid="B10" ref-type="bibr">10</xref>]).</p><p>In many cases, the dimerization of 14-3-3 proteins is crucial to their roles 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 agents, which may target monomeric 14-3-3 proteins [<xref rid="B16" ref-type="bibr">16</xref>]. 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 spatially regulating cell signaling [<xref rid="B17" ref-type="bibr">17</xref>–<xref rid="B21" ref-type="bibr">21</xref>].</p><p>14-3-3 proteins bind to substrate proteins through phosphodependent and phosphoindependent interactions [<xref rid="B22" ref-type="bibr">22</xref>, <xref rid="B23" ref-type="bibr">23</xref>]. To date more than 200 proteins have been found to interact with 14-3-3 family members, 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 [<xref rid="B9" ref-type="bibr">9</xref>, <xref rid="B24" ref-type="bibr">24</xref>, <xref rid="B25" ref-type="bibr">25</xref>]. 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.</p></sec><sec id="sec3"><title>3. 14-3-3 Proteins in Neurological Disorders</title><p>14-3-3 proteins play diverse physiological roles and interact with a multitude of substrate proteins during normal development and adulthood [<xref rid="B25" ref-type="bibr">25</xref>, <xref rid="B26" ref-type="bibr">26</xref>]. Furthermore, many lines of evidence have identified 14-3-3 proteins as important targets in neuropathological processes [<xref rid="B27" ref-type="bibr">27</xref>, <xref rid="B28" ref-type="bibr">28</xref>]. 14-3-3 proteins are detected in the cerebrospinal fluid in various neurodegenerative diseases, such as multiple sclerosis [<xref rid="B2" ref-type="bibr">2</xref>, <xref rid="B29" ref-type="bibr">29</xref>], Creutzfeldt-Jakob disease [<xref rid="B30" ref-type="bibr">30</xref>–<xref rid="B32" ref-type="bibr">32</xref>], and HIV-related neurodegeneration [<xref rid="B33" ref-type="bibr">33</xref>]. 14-3-3 proteins also serve as a biomarker of neurological disorders characterized by extensive destruction of neurons in the brain including acute stroke [<xref rid="B34" ref-type="bibr">34</xref>] and subarachnoidal hemorrhage [<xref rid="B35" ref-type="bibr">35</xref>]. 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 studied as potential biomarkers of neurodegeneration [<xref rid="B36" ref-type="bibr">36</xref>, <xref rid="B37" ref-type="bibr">37</xref>]. In addition, 14-3-3 proteins are found in disease-specific lesions and protein aggregates within the brain, and numerous studies have described 14-3-3 interactions with target proteins that regulate pathogenic processes [<xref rid="B3" ref-type="bibr">3</xref>, <xref rid="B27" ref-type="bibr">27</xref>, <xref rid="B28" ref-type="bibr">28</xref>]. This supports the notion that 14-3-3 proteins are involved in the pathogenesis of neurodegenerative disease in addition to their utility as general markers of tissue destruction. Because 14-3-3 proteins could define the subcellular localization of protein substrates, 14-3-3 detection in protein aggregates have encouraged a number of ideas including (1) 14-3-3 proteins may play a protective role through sequestration of toxic pathogenic proteins, (2) 14-3-3 proteins may be sequestered into aggregates resulting in their own loss of function, and (3) 14-3-3 proteins may facilitate formation of protein aggregates that cause a subsequent neurotoxicity. In addition to protein sorting, it is also known that 14-3-3 proteins stabilize their binding partners, protect phosphorylated species of target proteins, and regulate substrate enzyme activity. Failure of these functions could also contribute to neurodegenerative disease. Below, we discuss several specific examples implicating 14-3-3 proteins in the pathogenesis of neurodegenerative diseases.</p><sec id="sec3.1"><title>3.1. Parkinson's Disease</title><p>Parkinson's disease (PD) is an age-related neurodegenerative disease characterized by loss of dopaminergic neurons in the substantia nigra pars compacta [<xref rid="B38" ref-type="bibr">38</xref>]. PD is clinically characterized by progressive rigidity, bradykinesia, tremor, and postural instability [<xref rid="B39" ref-type="bibr">39</xref>]. Abnormal protein aggregates called Lewy bodies develop in neurons and are a pathological hallmark of PD. Lewy bodies are present in the brainstem, particularly in the substantia nigra [<xref rid="B40" ref-type="bibr">40</xref>, <xref rid="B41" ref-type="bibr">41</xref>]. The main component of Lewy bodies is <italic>α</italic>-synuclein, a regulator of the mitogen-activated protein kinase (MAPK) pathway, which plays an important role in dopamine synthesis [<xref rid="B42" ref-type="bibr">42</xref>–<xref rid="B44" ref-type="bibr">44</xref>]. Families with gene multiplication of <italic>α</italic>-synuclein exhibit autosomal dominant PD [<xref rid="B45" ref-type="bibr">45</xref>] and <italic>α</italic>-synuclein overexpression in an animal model leads to neuronal cell death [<xref rid="B46" ref-type="bibr">46</xref>]. Interestingly, expression levels of 14-3-3 <italic>γ</italic>, <italic>ε</italic>, and <italic>θ</italic> were reduced by <italic>α</italic>-synuclein overexpression in an animal model [<xref rid="B47" ref-type="bibr">47</xref>]. Conversely, overexpression of 14-3-3 <italic>ε</italic>, <italic>γ</italic>, and <italic>θ</italic> suppressed the aggregation of <italic>α</italic>-synuclein and decreased toxicity induced by rotenone or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) [<xref rid="B47" ref-type="bibr">47</xref>], two neurotoxins that cause cell death in dopaminergic cells and induce parkinsonian syndrome [<xref rid="B48" ref-type="bibr">48</xref>]. These observations are consistent with a model whereby <italic>α</italic>-synuclein could exert its effects at a transcriptional level by reducing the expression of 14-3-3 proteins contributing to pathogenesis in PD.</p><p>Immunohistochemical investigation has described intense 14-3-3 staining in Lewy bodies [<xref rid="B49" ref-type="bibr">49</xref>]. In particular, <italic>ε</italic>, <italic>γ</italic>, <italic>ζ</italic>, and <italic>θ</italic> isoforms were present, while <italic>β</italic>, <italic>η</italic>, and <italic>σ</italic> were not detectable in Lewy bodies [<xref rid="B50" ref-type="bibr">50</xref>]. <italic>α</italic>-synuclein was shown to bind to 14-3-3 proteins and to share amino acid sequence homology with 14-3-3 proteins [<xref rid="B51" ref-type="bibr">51</xref>], suggesting that 14-3-3 proteins may be related to <italic>α</italic>-synuclein aggregation. Indeed, 14-3-3 and <italic>α</italic>-synuclein can be coimmunoprecipitated from mammalian brains [<xref rid="B52" ref-type="bibr">52</xref>], and coimmunoprecipitation is increased in PD brains [<xref rid="B53" ref-type="bibr">53</xref>]. This raises the possibility that interaction between 14-3-3s and <italic>α</italic>-synuclein could have pathogenic roles that are independent of regulating 14-3-3 expression.</p><p>There is some evidence that a specific relevant target of 14-3-3 dysregulation may be in neuronal apoptosis in PD (Figures <xref ref-type="fig" rid="fig1">1(a)</xref> and <xref ref-type="fig" rid="fig2">2</xref>). 14-3-3 <italic>θ</italic> interacts with Bad, which is a negative regulator of the antiapoptotic molecule Bcl-2 in mitochondria [<xref rid="B54" ref-type="bibr">54</xref>]. 14-3-3 proteins can function as antiapoptotic factors by sequestering Bad protein in the cytoplasm leaving Bcl-2 function unobstructed [<xref rid="B54" ref-type="bibr">54</xref>]. Association of 14-3-3 proteins with <italic>α</italic>-synuclein reduced the antiapoptotic activity of Bcl-2 by increasing the levels of Bad protein in mitochondria. 14-3-3 proteins also work as antiapoptotic factors by binding Bcl-2-associated X protein (Bax), which promotes apoptosis upon translocation into mitochondria [<xref rid="B55" ref-type="bibr">55</xref>]. 14-3-3 <italic>θ</italic> prevents Bax translocation to the mitochondria and subsequent destruction of the mitochondrial outer membrane. Overexpression of 14-3-3 <italic>θ</italic> reduces dopaminergic cell death in cultured neurons exposed to rotenone and 1-methyl-4-phenylpyridinium (MPP+) and this effect was dependent on binding to Bax, supporting the idea that 14-3-3 proteins are antiapoptotic and may be targeted to promote neuronal survival in PD [<xref rid="B56" ref-type="bibr">56</xref>]. Indeed, there is a selective increase in 14-3-3/<italic>α</italic>-synuclein complex formation in the substantia nigra of patients with PD rendering the cell more susceptible to apoptosis [<xref rid="B52" ref-type="bibr">52</xref>]. One model is that sequestration of 14-3-3 proteins through interaction with <italic>α</italic>-synuclein results in the loss of appropriate 14-3-3 function contributing to the pathogenesis of PD (<xref ref-type="fig" rid="fig1">Figure 1(d)</xref>). The sequestration hypothesis could be relevant to antiapoptotic 14-3-3 substrates and/or other interacting partners with roles in PD pathogenesis.</p><p>Additionally, 14-3-3 proteins play a role in the dopaminergic signaling pathway in PD (<xref ref-type="fig" rid="fig1">Figure 1(b)</xref>). Dopaminergic neuronal cell death with a reduction of brain dopamine is one of the main features of PD. 14-3-3 <italic>ζ</italic> binds to phosphorylated tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis, and leads to prolonged activation of the enzyme [<xref rid="B57" ref-type="bibr">57</xref>–<xref rid="B59" ref-type="bibr">59</xref>]. <italic>α</italic>-synuclein reduces the activity of tyrosine hydroxylase and subsequent dopamine production through binding to dephosphorylated tyrosine hydroxylase [<xref rid="B44" ref-type="bibr">44</xref>]. An intriguing idea is that 14-3-3 proteins may be targeted therapeutically to upregulate dopamine production and ease the progression of dopamine loss in PD.</p><p>Another isoform, 14-3-3 <italic>η</italic>, has been shown to bind and negatively regulate parkin, an E3 ubiquitin ligase that is mutated in a familial form of PD [<xref rid="B60" ref-type="bibr">60</xref>]. Parkin mediates the targeting of proteins for degradation and its loss of function is thought to result in the accumulation of proteins that are toxic to dopaminergic neurons [<xref rid="B53" ref-type="bibr">53</xref>, <xref rid="B61" ref-type="bibr">61</xref>]. The interaction between 14-3-3 and parkin is disrupted when parkin has a mutation that causes autosomal recessive juvenile parkinsonism [<xref rid="B53" ref-type="bibr">53</xref>]. Further, <italic>α</italic>-synuclein abrogates 14-3-3 <italic>η</italic>-related parkin inactivation [<xref rid="B53" ref-type="bibr">53</xref>]. While it is not clear how these interactions ultimately regulate neuronal parkin activity, these findings suggest potential functional significance for 14-3-3 <italic>η</italic> in PD pathogenesis.</p><p>Variants in Leucine-rich repeat kinase 2 (LRRK2) are associated with an increased risk in PD [<xref rid="B62" ref-type="bibr">62</xref>]. Although little is understood about its physiological function in PD pathogenesis, it was recently shown to bind to several 14-3-3 isoforms [<xref rid="B63" ref-type="bibr">63</xref>]. A common mutation of familial PD in LRRK2 abolished the interaction between 14-3-3 and LRRK2 [<xref rid="B64" ref-type="bibr">64</xref>]. Disruption of the interaction between 14-3-3 and LRRK2 led to LRRK2 accumulation within cytoplasmic pools rather than a normal diffuse localization throughout the cell [<xref rid="B65" ref-type="bibr">65</xref>]. 14-3-3 proteins might stabilize LRRK2 in the cytoplasm preventing its aggregation. Further evidence suggests that disrupting the 14-3-3-LRRK2 interaction blocks the release of LRRK2 into extracellular microvesicles [<xref rid="B66" ref-type="bibr">66</xref>]. A number of lines of evidence suggest that aberrant LRRK2 protein sorting in neurons may contribute to PD pathogenesis (<xref ref-type="fig" rid="fig1">Figure 1(c)</xref>). For example, Rab7L1 regulates the intraneuronal sorting of LRRK2 and also <italic>Rab7L1</italic> gene is located in a locus harboring PD susceptibility [<xref rid="B67" ref-type="bibr">67</xref>, <xref rid="B68" ref-type="bibr">68</xref>]. Reduced neurite extension in cultured neurons harboring mutant LRRK2 can be rescued by overexpression of Rab7L1 supporting the idea that proper sorting is critical to its function [<xref rid="B67" ref-type="bibr">67</xref>]. 14-3-3 proteins may act in a similar fashion to regulate intracellular LRRK2 protein localization.</p><p>Together, these studies demonstrate that multiple 14-3-3 isoforms are involved in pathogenic processes of PD, including apoptosis, aberrant dopamine production, and protein sorting.</p></sec><sec id="sec3.2"><title>3.2. Amyotrophic Lateral Sclerosis</title><p>Amyotrophic lateral sclerosis (ALS) is a rapidly progressing fatal motor neuron disease for which a precise cause has not yet been identified. It is characterized by muscle weakness and atrophy that results in difficulties in breathing, swallowing, and speaking [<xref rid="B69" ref-type="bibr">69</xref>]. A neuropathological hallmark of ALS is the presence of intraneuronal neurofilament aggregates [<xref rid="B70" ref-type="bibr">70</xref>]. Neurofilament proteins are highly conserved neuronal intermediate filaments characterized on the basis of molecular weight and are composed of a light, medium, and heavy molecular weight isoforms (NF-L, NF-M, and NF-H). The assembly of the filamentous neurofilament complex is dependent on the primary homopolymerization of NF-L, and the stoichiometry of neurofilament subunits is highly regulated [<xref rid="B71" ref-type="bibr">71</xref>]. Alterations in the stoichiometry are associated with neurofilament aggregate formation in a variety of transgenic models of motor neuron degeneration [<xref rid="B72" ref-type="bibr">72</xref>]. NF-L mRNA levels are selectively reduced in degenerating spinal motor neurons in ALS patients [<xref rid="B73" ref-type="bibr">73</xref>] and this may be of specific relevance to the genesis of neurofilament aggregates in ALS. NF-L mRNA are stabilized through binding with several proteins, such as 14-3-3, TAR DNA binding protein (TDP-43) and copper/zinc superoxide dismutase (SOD) [<xref rid="B74" ref-type="bibr">74</xref>, <xref rid="B75" ref-type="bibr">75</xref>]. In both familial ALS and an ALS animal model, 14-3-3 <italic>β</italic> and <italic>γ</italic> are present in Lewy body-like hyaline inclusions (LBHI) [<xref rid="B76" ref-type="bibr">76</xref>]. TDP-43, and SOD were also identified as a component of LBHI [<xref rid="B77" ref-type="bibr">77</xref>, <xref rid="B78" ref-type="bibr">78</xref>]. Together, this supports a model whereby the formation of LBHI could sequester proteins that favor the stabilization of NF-L mRNA, leading to neurofilament aggregates in ALS. Furthermore, recent work revealed that 14-3-3 interacts with NF-L in an NF-L-phosphorylation-dependent manner and diminished 14-3-3 interaction with NF-L resulted in the formation of neurofilament aggregation [<xref rid="B79" ref-type="bibr">79</xref>]. The data is consistent with a central role of 14-3-3 proteins in quality control of neurofilaments through regulating stoichiometry and preventing aggregate formation in ALS.</p><p>Other studies have shown that mRNA for 14-3-3 <italic>ζ</italic> and <italic>θ</italic> are upregulated following hypoglossal nerve injury in rats and that 14-3-3 <italic>θ</italic> is upregulated in the spinal cord of ALS patients [<xref rid="B80" ref-type="bibr">80</xref>, <xref rid="B81" ref-type="bibr">81</xref>]. Proteomic analysis from spinal cord tissue from ALS patients identified elevated expression and/or activation of many protein kinases, including protein kinase C (PKC), glycogen synthesis kinase 3<italic>β</italic> (GSK3<italic>β</italic>), calcium-calmodulin-dependent protein kinase kinase (CAMKK), Akt, S6 K, and protein kinase A (PKA), which may augment neural death in ALS [<xref rid="B82" ref-type="bibr">82</xref>]. An intriguing idea is that upregulated 14-3-3 proteins could function to sequester hyperphosphorylated substrates or kinases, attenuating the effects of elevated kinases and playing a neuroprotective role in ALS. For example, 14-3-3 <italic>β</italic> and <italic>γ</italic> are able to interact with PKA subunits and inhibit PKA activation [<xref rid="B83" ref-type="bibr">83</xref>].</p></sec><sec id="sec3.3"><title>3.3. Alzheimer Disease</title><p>Alzheimer disease (AD) is a common form of progressive dementia neuropathologically characterized by cortical and perivascular amyloid plaques and neurofibrillary tangles (NFTs). NFTs are composed of paired helical filaments with the microtubule-associated protein tau as a main component [<xref rid="B84" ref-type="bibr">84</xref>]. Tau, a major microtubule-associated protein in neurons, binds and stabilizes microtubules. Tau phosphorylation reduces its affinity for microtubules and tau is hyperphosphorylated in AD. Phosphorylation is thought to cause loss of tau function, instability of the microtubule, formation of NFTs, and neurodegeneration [<xref rid="B84" ref-type="bibr">84</xref>, <xref rid="B85" ref-type="bibr">85</xref>]. 14-3-3 proteins have been detected in NFT of AD patients with 14-3-3 <italic>ζ</italic> being the most highly immunoreactive [<xref rid="B15" ref-type="bibr">15</xref>]. Further study has demonstrated that 14-3-3 <italic>ζ</italic> facilitates GSK3<italic>β</italic>-dependent phosphorylation of tau by enhancing the affinity of GSK3<italic>β</italic> for tau [<xref rid="B86" ref-type="bibr">86</xref>, <xref rid="B87" ref-type="bibr">87</xref>]. It is also noteworthy that proteins bound to 14-3-3 <italic>ζ</italic> are relatively resistant to protein phosphatases, raising the possibility that 14-3-3 <italic>ζ</italic> may enhance the strength or duration of kinase-dependent signals in pathogenic circumstances [<xref rid="B87" ref-type="bibr">87</xref>]. However, it has also been shown that 14-3-3 <italic>β</italic>, <italic>η</italic>, and <italic>ζ</italic> bind with high affinity to tau that has been phosphorylated by Akt and PKA [<xref rid="B88" ref-type="bibr">88</xref>] and this interaction reduced the aggregation of tau <italic>in vitro</italic>. On the contrary, tau phosphorylated by GSK3<italic>β</italic> rapidly aggregated [<xref rid="B88" ref-type="bibr">88</xref>]. Thus it appears that 14-3-3 proteins can have dual roles in tau aggregation and their global effects are likely to be context dependent.</p><p>Reactivation of the cell cycle in AD neurons is a potential mechanism that drives cells towards neuronal atrophy [<xref rid="B89" ref-type="bibr">89</xref>–<xref rid="B91" ref-type="bibr">91</xref>]. There is some evidence that 14-3-3 proteins may play a neuroprotective role through this molecular pathway. There is evidence that activity of the cell cycle kinase Cdk5 and the cell cycle phosphatase Cdc25 are increased in clinical AD samples [<xref rid="B92" ref-type="bibr">92</xref>, <xref rid="B93" ref-type="bibr">93</xref>]. Inhibition of Cdk5 or Cdc25 promoted neuroprotection in cultured neurons treated with an oligomeric amyloid <italic>β</italic> 1–42 (A<italic>β</italic>42), one of toxic species in AD brain [<xref rid="B94" ref-type="bibr">94</xref>]. Intriguingly, 14-3-3 <italic>ε</italic> binds Cdc25 and sequesters it in the cytoplasm, and A<italic>β</italic>42 diminished this interaction [<xref rid="B94" ref-type="bibr">94</xref>]. When the interaction between Cdc25 and 14-3-3 <italic>ε</italic> is inhibited through Cdk5-mediated phosphorylation of Cdc25, neurotoxicity and neuronal death are promoted in AD [<xref rid="B94" ref-type="bibr">94</xref>] (<xref ref-type="fig" rid="fig2">Figure 2</xref>).</p><p>Serine-arginine protein kinase 2 (SRPK2) is a cell cycle-regulated protein kinase, which can translocate into the nucleus and promote cyclin D1 upregulation and cell cycle reentry [<xref rid="B95" ref-type="bibr">95</xref>] (<xref ref-type="fig" rid="fig2">Figure 2</xref>). 14-3-3 <italic>β</italic>, <italic>ε</italic>, and <italic>σ</italic> interact SRPK2 and inhibit its translocation into the nucleus [<xref rid="B95" ref-type="bibr">95</xref>]. In an AD mouse model, depletion of SRPK2 in the dentate gyrus alleviated impaired cognitive behaviors and defective LTP [<xref rid="B96" ref-type="bibr">96</xref>]. Together, these observations support the idea that 14-3-3 proteins can suppress the functions of many critical substrates that have been implicated in cell cycle reentry of neurons in AD.</p><p>Finally, 14-3-3 proteins may directly regulate apoptotic pathways in AD. Active Cdk1 promotes neuronal death in postmitotic granule neurons by phosphorylating the forkhead box, group O 1 (FOXO1) transcription factor upon depolarization [<xref rid="B97" ref-type="bibr">97</xref>]. FOXO1 is also a binding partner of 14-3-3 <italic>β</italic> [<xref rid="B97" ref-type="bibr">97</xref>]. Phosphorylated FOXO1 dissociates from 14-3-3 and translocates into the nucleus where FOXO1-dependent transcription induces neuronal cell death [<xref rid="B97" ref-type="bibr">97</xref>]. This finding also suggests that 14-3-3 proteins play a positive role in promoting neuronal cell survival and could protect against AD pathogenesis; however, direct experiments to test this hypothesis in an AD model remain to be done (<xref ref-type="fig" rid="fig2">Figure 2</xref>).</p></sec><sec id="sec3.4"><title>3.4. Creutzfeldt-Jakob Disease</title><p>Creutzfeldt-Jakob disease (CJD) is a neurodegenerative disorder clinically characterized by a rapidly progressive dementia and a characteristic combination of neurological features [<xref rid="B98" ref-type="bibr">98</xref>, <xref rid="B99" ref-type="bibr">99</xref>]. Classic CJD occurs sporadically through the transformation of prion proteins into abnormal species. The definite diagnosis of CJD can only be made histopathologically; thus, the identification of diagnostic markers for CJD is an unmet need. Several studies confirmed that 14-3-3 proteins from cerebrospinal fluid (CSF) may be reliable markers for CJD [<xref rid="B30" ref-type="bibr">30</xref>, <xref rid="B31" ref-type="bibr">31</xref>]. The total content of 14-3-3 protein was significantly higher in the CSF of patients with definite or probable CJD than in patients with other neurodegenerative disorders [<xref rid="B102" ref-type="bibr">100</xref>]. Extensive destruction of neurons in brain in CJD may result in leakage of 14-3-3 proteins into the CSF, but the specific link to CJD also raises the possibility that 14-3-3 proteins play specific roles in the pathogenesis of CJD. 14-3-3 <italic>ζ</italic> was detected in amyloid plaques of sporadic and variant CJD, while other isoforms were absent from these deposits [<xref rid="B103" ref-type="bibr">101</xref>].</p></sec><sec id="sec3.5"><title>3.5. Polyglutamine Disease</title><p>Spinocerebellar ataxia type 1 (SCA1) is a lethal neurodegenerative disorder caused by expansion of a polyglutamine (poly-Q) tract in ataxin-1 [<xref rid="B104" ref-type="bibr">102</xref>]. A prominent site of pathology in SCA1 is cerebellar Purkinje neurons where mutant ataxin-1 enter the nucleus and aggregates in inclusion bodies (IB) [<xref rid="B105" ref-type="bibr">103</xref>, <xref rid="B106" ref-type="bibr">104</xref>]. While wild type ataxin-1 shuttles back and forth between nucleus and cytoplasm, ataxin-1 with a poly-Q tract fails to properly transport back to the cytoplasm after entry into the nucleus [<xref rid="B107" ref-type="bibr">105</xref>]. Although nuclear IB were identified as a pathological hall mark primarily in the affected brain regions, several studies suggest that the function of IB is neuroprotective [<xref rid="B108" ref-type="bibr">106</xref>, <xref rid="B109" ref-type="bibr">107</xref>]. 14-3-3 <italic>β</italic>, <italic>ζ</italic>, and <italic>ε</italic> proteins bind to phosphorylated ataxin-1 and impede its translocation into the nucleus, prevent its dephosphorylation, and stabilize the protein [<xref rid="B110" ref-type="bibr">108</xref>]. 14-3-3 could therefore be playing dual functions on SCA1 pathogenesis. 14-3-3 interactions with ataxin-1 may play a positive role in inhibiting ataxin-1 translocation to the nucleus or it could play a negative role by stabilizing ataxin-1 harboring a poly-Q tract. The finding that a partial loss of 14-3-3 <italic>ε</italic> improves cerebellar phenotypes in SCA1 suggests that 14-3-3 contributes to the pathogenesis of SCA1 [<xref rid="B111" ref-type="bibr">109</xref>].</p><p>Huntington's disease (HD) is an autosomal dominant progressive neurodegenerative disorder caused by poly-Q expansions in the Huntingtin protein [<xref rid="B112" ref-type="bibr">110</xref>]. 14-3-3 <italic>ζ</italic> might scavenge misfolded Huntingtin proteins by facilitating the formation of aggregates possibly for neuroprotection [<xref rid="B113" ref-type="bibr">111</xref>]; these aggregates are referred to as IBs in Huntington's disease. Huntingtin with a poly-Q tract also forms IB, but 14-3-3 reduction by siRNA abolished Huntingtin IB formation [<xref rid="B114" ref-type="bibr">112</xref>], suggesting 14-3-3 participates in Huntingtin IB formation.</p></sec><sec id="sec3.6"><title>3.6. Excitotoxicity Dependent Neurodegeneration</title><p>Temporal lobe epilepsy is a common type of human epilepsy characterized by extensive loss of hippocampal pyramidal neurons and associated gliosis. Frequent seizures lead to neuronal cell death, which may be caused by the apoptotic cell death pathway [<xref rid="B115" ref-type="bibr">113</xref>]. The subcellular distribution and expression levels of 14-3-3 proteins are also regulated by seizure activity raising the possibility that antiapoptotic 14-3-3 functions could be disrupted by seizures [<xref rid="B116" ref-type="bibr">114</xref>, <xref rid="B117" ref-type="bibr">115</xref>].</p><p>Apoptosis signal-regulating kinase 1 (ASK1) is mitogen-activated protein kinase kinase kinase (MAPKKK), which plays a pivotal role in cell apoptosis [<xref rid="B118" ref-type="bibr">116</xref>]. ASK1 is weakly expressed in the hippocampus from control brains but is enhanced 4–24 hr after seizures [<xref rid="B119" ref-type="bibr">117</xref>]. 14-3-3 <italic>β</italic> binds and inhibits the activity of ASK1 [<xref rid="B119" ref-type="bibr">117</xref>]. Notably, ASK1 dissociates from 14-3-3 protein after seizures [<xref rid="B119" ref-type="bibr">117</xref>]. Although the precise mechanism by which 14-3-3s may regulate ASK1 remains to be determined, it is reasonable to speculate that dissociation of the 14-3-3-ASK1 complex promotes apoptosis.Further, reduction of 14-3-3 expression leads to activation of Bad protein after the seizure, further demonstrating how a pathological condition may circumvent the antiapoptotic role of 14-3-3 proteins [<xref rid="B119" ref-type="bibr">117</xref>] (<xref ref-type="fig" rid="fig2">Figure 2</xref>).</p><p>Ischemic injury in the central nervous system causes neurodegeneration by neuronal apoptosis. A recurring theme in this paper is the role of 14-3-3 interactions with proapoptotic proteins in preventing neuronal apoptosis. After ischemia, Bad and Bax dissociated from 14-3-3 <italic>ζ</italic> and translocated to the mitochondria to suppress the antiapoptotic protein Bcl-2 [<xref rid="B120" ref-type="bibr">118</xref>, <xref rid="B121" ref-type="bibr">119</xref>]. Interestingly, a brief episode of sublethal ischemia followed by reperfusion prevents the lethal effect of subsequent periods of prolonged ischemia [<xref rid="B122" ref-type="bibr">120</xref>] and ischemic preconditioning limits 14-3-3-ASK1 dissociation and subsequent apoptotic signaling [<xref rid="B123" ref-type="bibr">121</xref>].</p><p>The same antiapoptotic function of 14-3-3 proteins has been reported in retinal ganglion cells (RGC) in a glaucoma model in rat. Elevated intraocular pressure leads to enhanced expression of 14-3-3 <italic>β</italic>, <italic>ζ</italic>, <italic>η</italic>, <italic>γ</italic>, and <italic>θ</italic> in RGCs [<xref rid="B124" ref-type="bibr">122</xref>]. Affinity pull-down analysis demonstrated that 14-3-3 proteins are associate with Bad in RGCs [<xref rid="B124" ref-type="bibr">122</xref>]. Thus, 14-3-3s may sequester Bad to the cytoplasm of RGCs, playing a neuroprotective role in experimental glaucoma.</p></sec><sec id="sec3.7"><title>3.7. Glia-Mediated Neurodegeneration</title><p>Multiple system atrophy (MSA) is a fatal multisystem progressive disorder characterized clinically by various combinations of autonomic failure, cerebellar symptoms, parkinsonism, and pyramidal signs [<xref rid="B125" ref-type="bibr">123</xref>]. Glial cytoplasmic inclusion (GCI) is a distinctive hallmark for MSA [<xref rid="B126" ref-type="bibr">124</xref>, <xref rid="B127" ref-type="bibr">125</xref>]. The GCI is immunopositive for <italic>α</italic>-synuclein [<xref rid="B128" ref-type="bibr">126</xref>, <xref rid="B129" ref-type="bibr">127</xref>] and is predominantly found in oligodendrocytes [<xref rid="B126" ref-type="bibr">124</xref>, <xref rid="B127" ref-type="bibr">125</xref>]. Accumulation of <italic>α</italic>-synuclein might be causally linked to the progression of MSA, because <italic>α</italic>-synuclein aggregation in oligodendrocytes may cause demyelination, resulting in initiation of neurodegeneration [<xref rid="B130" ref-type="bibr">128</xref>]. 14-3-3 proteins may play a role in <italic>α</italic>-synuclein accumulation in GCI. Immunohistochemical analyses revealed that both <italic>α</italic>-synuclein and 14-3-3 proteins are colocalized in the GCIs in MSA brains [<xref rid="B131" ref-type="bibr">129</xref>]. Similar to the PD pathogenesis, the interaction between 14-3-3 and <italic>α</italic>-synuclein may have a role in an aggregation of <italic>α</italic>-synuclein in oligodendrocytes, resulting in development of MSA.</p><p>Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS of autoimmune origin [<xref rid="B132" ref-type="bibr">130</xref>]. Although many aspects of MS pathogenesis have been elucidated, exact causal mechanisms are still not fully understood. Levels of 14-3-3 proteins have been shown to be increased in glial cells of MS patients [<xref rid="B133" ref-type="bibr">131</xref>]. In particular, 14-3-3 <italic>β</italic>, <italic>ε</italic>, <italic>ζ</italic>, and <italic>η</italic> are intensely expressed in reactive astrocytes in the demyelinating lesions of MS [<xref rid="B133" ref-type="bibr">131</xref>]. Protein overlay analyses and coimmunoprecipitation experiments showed that 14-3-3 <italic>β</italic>, <italic>ε</italic>, and <italic>ζ</italic> isoforms interact with vimentin and glial fibrillary acidic protein (GFAP) in astrocytes. Because these glial intermediate filament proteins are copolymerized in assembled filaments in reactive astrocytes [<xref rid="B134" ref-type="bibr">132</xref>, <xref rid="B135" ref-type="bibr">133</xref>], 14-3-3 protein may act as a bridge between vimentin and GFAP or as a bundle of vimentin with GFAP in the same filament. As reactive astrocytes release glutamate or proinflammatory cytokines to cause neuronal death [<xref rid="B136" ref-type="bibr">134</xref>, <xref rid="B137" ref-type="bibr">135</xref>], 14-3-3 proteins may contribute to the MS pathogenesis through stabilization of cytoskeletal networks in reactive astrocytes.</p></sec></sec><sec id="sec4"><title>4. Conclusion and Perspective</title><p>14-3-3 involvement in multiple cellular processes has prompted investigators to study their role in various pathological processes. Investigation into the numerous proteins and pathways that 14-3-3 proteins regulate is ongoing. Changes in 14-3-3 protein expression levels in the CNS and CSF of patients with neurodegenerative disease has spurred investigation into their utility as biomarkers and into their potential roles in specific pathologies.</p><p>Numerous studies suggest that 14-3-3 is involved in disease-associated apoptosis and pathologies in a variety of conditions including PD, ALS, AD, epilepsy, CJD, MSA, and MS. Isoform-specific histology and involvement in each disease mentioned in this review are summarized in <xref ref-type="table" rid="tab1">Table 1</xref>. Localization of specific 14-3-3 isoforms in protein aggregates suggest that 14-3-3 proteins participate in aggregate formation or that their normal protective functions may be disrupted through such aggregation. Antiapoptotic functions of 14-3-3 proteins through regulation of Bad and Bax protein translocation could play important neuroprotective roles. Thus, defining of subcellular localization of 14-3-3 interacting partners may be a major role of 14-3-3 proteins in the pathophysiological process of neurodegeneration.</p><p>The potential involvement of 14-3-3 proteins in various neurodegenerative diseases encourages future investigation to elucidate how 14-3-3s impact pathologies that are unique and common to each disease. Future studies will reveal relevant binding partners of 14-3-3 proteins in specific pathologies and may aid in the conception and validation of therapeutic targets to treat neurodegenerative conditions.</p></sec></body><back><ack><title>Conflict of Interests</title><p>The authors declare that there is no conflict of interests regarding the publication of this paper.</p></ack><ack><title>Acknowledgments</title><p>This work was partly supported by the JSPS KAKENHI Grant nos. 24700349, 24659093, and 25293239; MEXT KAKENHI Grant no. 25110737; and grants from the Canadian Institutes of Health Research and the McGill Program in Neuroengineering.</p></ack><ref-list><ref id="B1"><label>1</label><element-citation publication-type="book"><person-group person-group-type="author"><name><surname>Moore</surname><given-names>BW</given-names></name><name><surname>Perez</surname><given-names>VJ</given-names></name></person-group><person-group person-group-type="editor"><name><surname>Carlson</surname><given-names>FD</given-names></name></person-group><article-title>Specific acidic proteins of the nervous system</article-title><source><italic>Physiological and Biochemical Aspects of Nervous Integration</italic></source><year>1968</year><fpage>343</fpage><lpage>360</lpage></element-citation></ref><ref id="B2"><label>2</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Boston</surname><given-names>PF</given-names></name><name><surname>Jackson</surname><given-names>P</given-names></name><name><surname>Thompson</surname><given-names>RJ</given-names></name></person-group><article-title>Human 14-3-3 protein: radioimmunoassay, tissue distribution, and cerebrospinal fluid levels in patients with neurological disorders</article-title><source><italic>Journal of Neurochemistry</italic></source><year>1982</year><volume>38</volume><issue>5</issue><fpage>1475</fpage><lpage>1482</lpage><pub-id pub-id-type="other">2-s2.0-0020324478</pub-id><pub-id pub-id-type="pmid">7062063</pub-id></element-citation></ref><ref id="B3"><label>3</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Berg</surname><given-names>D</given-names></name><name><surname>Holzmann</surname><given-names>C</given-names></name><name><surname>Riess</surname><given-names>O</given-names></name></person-group><article-title>14-3-3 proteins in the nervous system</article-title><source><italic>Nature Reviews Neuroscience</italic></source><year>2003</year><volume>4</volume><issue>9</issue><fpage>752</fpage><lpage>762</lpage><pub-id pub-id-type="other">2-s2.0-0141722623</pub-id><pub-id pub-id-type="pmid">12951567</pub-id></element-citation></ref><ref id="B4"><label>4</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Martin</surname><given-names>H</given-names></name><name><surname>Patel</surname><given-names>Y</given-names></name><name><surname>Jones</surname><given-names>D</given-names></name><name><surname>Howell</surname><given-names>S</given-names></name><name><surname>Robinson</surname><given-names>K</given-names></name><name><surname>Aitken</surname><given-names>A</given-names></name></person-group><article-title>Antibodies against the major brain isoforms of 14-3-3 protein. 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Parkinson's disease. 14-3-3 proteins may play a protective role against neurodegeneration in PD by interacting with various proteins. (a) 14-3-3 interacts with Bad and Bax proteins and inhibits their translocation into mitochondria and their subsequent suppression of Bcl-2. These interactions prevent apoptosis of neurons. (b) 14-3-3 proteins interact with phosphorylated tyrosine hydroxylase (TH) to enhance its activity. In contrast, <italic>α</italic>-synuclein binds unphosphorylated TH to reduce its activity. These protein interactions contribute to the maintenance of optimal dopamine levels. Inadequate levels of dopamine lead to a neurodegeneration. (c) 14-3-3 interacts with LRRK2 protein that is related to PD pathogenesis. This interaction may inhibit cytosolic accumulation and secretion of LRRK2. (d) <italic>α</italic>-synuclein interacts with 14-3-3 proteins and forms aggregates, resulting in the sequestration of 14-3-3. This sequestration may contribute to the pathogenesis of PD.</p></caption><graphic xlink:href="BMRI2013-564534.001"></graphic></fig><fig id="fig2" orientation="portrait" position="float"><label>Figure 2</label><caption><p>Overview of the molecular basis of 14-3-3 antiapoptotic activity. 14-3-3 proteins inhibit apoptosis through multiple mechanisms including regulating the subcellular localization of pro- and antiapoptotic proteins. 14-3-3 binds to Bad and Bax to sequester them in the cytoplasm. Similarly, SRPK2 and FOXO1 are retained in the cytoplasm through 14-3-3 binding. Cdc25 is exported from the nucleus through a 14-3-3 interaction. SRPK2, FOXO1, and Cdc25 contribute to cell cycle reentry and subsequent apoptosis. Further, the death-promoting activity of ASK1 is antagonized by its binding to 14-3-3 proteins.</p></caption><graphic xlink:href="BMRI2013-564534.002"></graphic></fig><table-wrap id="tab1" orientation="portrait" position="float"><label>Table 1</label><caption><p>14-3-3 isoforms in neurodegeneration.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left" rowspan="1" colspan="1">14-3-3 isoform</th><th align="left" rowspan="1" colspan="1">Isoform-specific histology</th><th align="left" rowspan="1" colspan="1">Interacting partner and disease involvement</th></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1"><italic>β</italic></td><td align="left" rowspan="1" colspan="1">Tangles in AD<break></break>LBHI in ALS<break></break>GCI in MSA</td><td align="left" rowspan="1" colspan="1">LRRK2; PD<break></break>NFL mRNA; ALS<break></break>Tau, SPRK2, FOXO1; AD<break></break>Ataxin-1; SCA1<break></break>ASK1; Epilepsy<break></break>GFAP; MS</td></tr><tr><td align="left" colspan="3" rowspan="1"><hr></hr></td></tr><tr><td align="left" rowspan="1" colspan="1"><italic>γ</italic></td><td align="left" rowspan="1" colspan="1">Tangles in AD<break></break>Lewy bodies in PD<break></break>LBH in ALS<break></break>GCI in MSA</td><td align="left" rowspan="1" colspan="1">LRRK2; PD<break></break>NFL mRNA; ALS</td></tr><tr><td align="left" colspan="3" rowspan="1"><hr></hr></td></tr><tr><td align="left" rowspan="1" colspan="1"><italic>ε</italic></td><td align="left" rowspan="1" colspan="1">Tangles in AD<break></break>Lewy bodies in PD<break></break>GCI in MSA</td><td align="left" rowspan="1" colspan="1">LRRK2; PD<break></break>Cdc25, SPRK2; AD<break></break>Ataxin-1; SCA1<break></break>GFAP; MS</td></tr><tr><td align="left" colspan="3" rowspan="1"><hr></hr></td></tr><tr><td align="left" rowspan="1" colspan="1"><italic>ζ</italic></td><td align="left" rowspan="1" colspan="1">Tangles in AD<break></break>Lewy bodies in PD<break></break>Amyloid plaque in CJD<break></break>GCI in MSA</td><td align="left" rowspan="1" colspan="1">Tyrosine hydroxylase, LRRK2; PD <break></break>NFL mRNA; ALS<break></break>GSK3<italic>β</italic>, tau; AD<break></break>Ataxin-1; SCA1<break></break>Huntingtin; HD<break></break>Bad, Bax; Ischemia<break></break>GFAP; MS</td></tr><tr><td align="left" colspan="3" rowspan="1"><hr></hr></td></tr><tr><td align="left" rowspan="1" colspan="1"><italic>η</italic></td><td align="left" rowspan="1" colspan="1"> </td><td align="left" rowspan="1" colspan="1">Parkin, LRRK2; PD<break></break>NFL mRNA; ALS<break></break>Tau; AD</td></tr><tr><td align="left" colspan="3" rowspan="1"><hr></hr></td></tr><tr><td align="left" rowspan="1" colspan="1"><italic>σ</italic></td><td align="left" rowspan="1" colspan="1">Tangles in AD</td><td align="left" rowspan="1" colspan="1">SPRK2; AD</td></tr><tr><td align="left" colspan="3" rowspan="1"><hr></hr></td></tr><tr><td align="left" rowspan="1" colspan="1"><italic>θ</italic>/<italic>τ</italic></td><td align="left" rowspan="1" colspan="1">Lewy bodies in PD<break></break>GCI in MSA</td><td align="left" rowspan="1" colspan="1">Bad, Bax, LRRK2; PD<break></break>NFL mRNA; ALS</td></tr></tbody></table></table-wrap></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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