Nuclear localization of Cdk5 is a key determinant in the postmitotic state of neurons

Zhang, Jie; Cicero, Samantha A.; Wang, Li; Romito-DiGiacomo, Rita R.; Yang, Yan; Herrup, Karl

doi:10.1073/pnas.0711355105

Cited by 111 publications

(100 citation statements)

References 38 publications

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“…Indeed, in human LOAD, models incorporating the critical role of mitotic cells have been proposed, such as a “simple linear model” that states that human AD pathology develops from mitotic cycle‐reentering neurons that later die (Herrup, 2010), and the “two‐hit model” of human LOAD (Zhu, Lee, Perry, & Smith, 2007; Zhu, Raina, Perry, & Smith, 2004) that purports that LOAD development occurs with (a) oxidative stress and (b) mitotic reentry. Although the direct trigger for mitotic cycle reentry in Sgo1 −/+ model mice remains unclear, studies on roles of cell cycle regulators, such as Cdk5 (Zhang et al., 2008), and on effects of genes identified through RNA‐seq in this study on the cell cycle, are warranted.…”

Section: Discussionmentioning

confidence: 97%

Spontaneous development of Alzheimer's disease‐associated brain pathology in a Shugoshin‐1 mouse cohesinopathy model

et al. 2018

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SummarySpontaneous late‐onset Alzheimer's disease (LOAD) accounts for more than 95% of all human AD. As mice do not normally develop AD and as understanding on molecular processes leading to spontaneous LOAD has been insufficient to successfully model LOAD in mouse, no mouse model for LOAD has been available. Existing mouse AD models are all early‐onset AD (EOAD) models that rely on forcible expression of AD‐associated protein(s), which may not recapitulate prerequisites for spontaneous LOAD. This limitation in AD modeling may contribute to the high failure rate of AD drugs in clinical trials. In this study, we hypothesized that genomic instability facilitates development of LOAD and tested two genomic instability mice models in the brain pathology at the old age. Shugoshin‐1 (Sgo1) haploinsufficient (∓) mice, a model of chromosome instability (CIN) with chromosomal and centrosomal cohesinopathy, spontaneously exhibited a major feature of AD pathology; amyloid beta accumulation that colocalized with phosphorylated Tau, beta‐secretase 1 (BACE), and mitotic marker phospho‐Histone H3 (p‐H3) in the brain. Another CIN model, spindle checkpoint‐defective BubR1−/+ haploinsufficient mice, did not exhibit the pathology at the same age, suggesting the prolonged mitosis‐origin of the AD pathology. RNA‐seq identified ten differentially expressed genes, among which seven genes have indicated association with AD pathology or neuronal functions (e.g., ARC, EBF3). Thus, the model represents a novel model that recapitulates spontaneous LOAD pathology in mouse. The Sgo1−/+ mouse may serve as a novel tool for investigating mechanisms of spontaneous progression of LOAD pathology, for early diagnosis markers, and for drug development.

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Section: Discussionmentioning

confidence: 97%

Spontaneous development of Alzheimer's disease‐associated brain pathology in a Shugoshin‐1 mouse cohesinopathy model

et al. 2018

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“…Moreover, CDK5 protein expression levels were significantly decreased upon loss of OGT. CDK5 represses neuronal cell-cycle advancement (40) and is an important upstream regulator of oxidative stress through phosphorylation of peroxiredoxin I/II and p53 (39). Interestingly, a recent paper suggests that blocking O-GlcNAcylation of CDK5 can lead to neuronal apoptosis by enhancing its association with the p53 pathway (41).…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, a recent paper suggests that blocking O-GlcNAcylation of CDK5 can lead to neuronal apoptosis by enhancing its association with the p53 pathway (41). Several other studies have implicated aberrant cell-cycle advancement in ADassociated neurodegeneration through deregulation of CDK5 levels and activity (40,42). Together, these results suggest that a major mode by which OGT ablation leads to neurodegeneration is through cell-cycle dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Loss of O -GlcNAc glycosylation in forebrain excitatory neurons induces neurodegeneration

Wang

Jensen

Rexach

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

158

137

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O-GlcNAc glycosylation (or O-GlcNAcylation) is a dynamic, inducible posttranslational modification found on proteins associated with neurodegenerative diseases such as α-synuclein, amyloid precursor protein, and tau. Deletion of the O-GlcNAc transferase (ogt) gene responsible for the modification causes early postnatal lethality in mice, complicating efforts to study O-GlcNAcylation in mature neurons and to understand its roles in disease. Here, we report that forebrain-specific loss of OGT in adult mice leads to progressive neurodegeneration, including widespread neuronal cell death, neuroinflammation, increased production of hyperphosphorylated tau and amyloidogenic Aβ-peptides, and memory deficits. Furthermore, we show that human cortical brain tissue from Alzheimer’s disease patients has significantly reduced levels of OGT protein expression compared with cortical tissue from control individuals. Together, these studies indicate that O-GlcNAcylation regulates pathways critical for the maintenance of neuronal health and suggest that dysfunctional O-GlcNAc signaling may be an important contributor to neurodegenerative diseases.

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“…However, when Cdk5 is dysregulated by calpain-mediated cleavage of p35 to p25, the C-terminal fragment of p35, hyperactive p25-Cdk5 translocates to the nucleus, leading to cell death in neurodegenerative diseases (Patrick et al, 1999;Gong et al, 2003;Smith et al, 2006;Saito et al, 2007;Kim et al, 2008;Wen et al, 2008;Chang et al, 2011). In contrast, several reports also implicate p35 in nuclear Cdk5 activity, indicated by the presence of nuclear p35-Cdk5 complexes (Qu et al, 2002;Fu et al, 2004;Zhang et al, 2008). For a comprehensive understanding of Cdk5 function, it is important to determine how cytoplasmic and nuclear localization of active Cdk5 is regulated.…”

Section: Introductionmentioning

confidence: 85%

“…These results indicate that a certain amount of p35 and p39 can enter into the nucleus. Nuclear Cdk5 or nuclear free p35 is suggested to prevent re-entry of postmitotic neurons into cell cycle (Zhang et al, 2008;Zhang et al, 2010). On the other hand, it is well documented that dysregulation of Cdk5 activity by cleavage of p35 to p25 by calpain induces neuronal death (Patrick et al, 1999;Gong et al, 2003;Smith et al, 2006;Saito et al, 2007;Kim et al, 2008;Wen et al, 2008;Chang et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Cdk5 phosphorylation of its activators p35 and p39 determines subcellular location of the holokinase in a phosphorylation site-specific manner

Asada¹,

Saito²,

Hisanaga³

2012

Journal of Cell Science

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SummaryCdk5 is a member of the cyclin-dependent kinase (Cdk) family, which is activated by neuronal activators p35 or p39. Cdk5 regulates a variety of neuronal activities including migration, synaptic activity and neuronal death. p35 and p39 impart cytoplasmic membrane association of p35-Cdk5 and p39-Cdk5, respectively, through their myristoylation, but it is not clearly understood how the cellular localization is related to different functions. We investigated the role of Cdk5 activity in the subcellular localization of p35-Cdk5 and p39-Cdk5. Cdk5 activity affected the localization of p35-Cdk5 and p39-Cdk5 through phosphorylation of p35 or p39. Using unphosphorylated or phosphomimetic mutants of p35 and p39, we found that phosphorylation at Ser8, common to p35 and p39, by Cdk5 regulated the cytoplasmic localization and perinuclear accumulation of unphosphorylated S8A mutants, and whole cytoplasmic distribution of phosphomimetic S8E mutants. Cdk5 activity was necessary to retain Cdk5-activator complexes in the cytoplasm. Nevertheless, small but distinct amounts of p35 and p39 were detected in the nucleus. In particular, nuclear p35 and p39 were increased when the Cdk5 activity was inhibited. p39 had a greater propensity to accumulate in the nucleus than p35, and phosphorylation at Thr84, specific to p39, regulated the potential nuclear localization activity of the Lys cluster in p39. These results suggest that the subcellular localization of the Cdk5-activator complexes is determined by its kinase activity, and also implicate a role for p39-Cdk5 in the nucleus.

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Nuclear localization of Cdk5 is a key determinant in the postmitotic state of neurons

Cited by 111 publications

References 38 publications

Spontaneous development of Alzheimer's disease‐associated brain pathology in a Shugoshin‐1 mouse cohesinopathy model

Spontaneous development of Alzheimer's disease‐associated brain pathology in a Shugoshin‐1 mouse cohesinopathy model

Loss of O -GlcNAc glycosylation in forebrain excitatory neurons induces neurodegeneration

Cdk5 phosphorylation of its activators p35 and p39 determines subcellular location of the holokinase in a phosphorylation site-specific manner

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