A novel CDK5-dependent pathway for regulating GSK3 activity and kinesin-driven motility in neurons

Morfini, Gerardo; Szebenyi, Györgyi; Brown, Hannah J.; Pant, Harish C.; Pigino, Gustavo; DeBoer, Scott R.; Beffert, Uwe; Brady, Scott T.

doi:10.1038/sj.emboj.7600237

Cited by 247 publications

(263 citation statements)

References 77 publications

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“…Lee et al [27] reported that the KCl-induced dephosphorylation of GSK3β in SH-SY5Y cells could be blocked by the PP1/PP2A inhibitor okadaic acid and the PP2B inhibitor cyclosporine A [27]. However, in that study, 30 nM okadaic acid was used, which is well above the IC50 values of okadaic acid for PP1 (10 nM) and PP2 (0.1 nM) [34], thus making okadaic acid a broadlyspecific phosphatase inhibitor. Therefore, it is likely that PP1 also is involved in dephosphorylating GSK3β following KCl treatment.…”

Section: Resultsmentioning

confidence: 88%

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The protein phosphatase-1/inhibitor-2 complex differentially regulates GSK3 dephosphorylation and increases sarcoplasmic/endoplasmic reticulum calcium ATPase 2 levels

King¹,

Gandy²,

Bijur³

2006

Experimental Cell Research

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The ubiquitously expressed protein glycogen synthase kinase-3 (GSK3) is constitutively active, however its activity is markedly diminished following phosphorylation of Ser21 of GSK3α and Ser9 of GSK3β. Although several kinases are known to phosphorylate Ser21/9 of GSK3, for example Akt, relatively much less is known about the mechanisms that cause the dephosphorylation of GSK3 at Ser21/9. In the present study KCl-induced plasma membrane depolarization of SH-SY5Y cells, which increases intracellular calcium concentrations caused a transient decrease in the phosphorylation of Akt at Thr308 and Ser473, and GSK3 at Ser21/9. Overexpression of the selective protein phosphatase-1 inhibitor protein, inhibitor-2, increased basal GSK3 phosphorylation at Ser21/9 and significantly blocked the KCl-induced dephosphorylation of GSK3β, but not GSK3α. The phosphorylation of Akt was not affected by the overexpression of inhibitor-2. GSK3 activity is known to affect sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2) levels. Overexpression of inhibitor-2 or treatment of cells with the GSK3 inhibitors lithium and SB216763 increased the levels of SERCA2. These results indicate that the protein phosphatase-1/inhibitor-2 complex differentially regulates GSK3 dephosphorylation induced by KCl and that GSK3 activity regulates SERCA2 levels. KeywordsAkt; glycogen synthase kinase-3; inhibitor-2; protein phosphatase-1; sarcoplasmic/endoplasmic reticulum calcium ATPase

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Section: Resultsmentioning

confidence: 88%

“…The regulation of Ser21/9 phosphorylation has been attributed to the actions of protein phosphatase-2A (PP2A) [40,43,27,38] and protein phosphatase-1 (PP1) [46,34,41]. The PP1 holoenzyme is comprised of a 37 kDa catalytic subunit which associates with inhibitory subunits and targeting subunits.…”

Section: Introductionmentioning

confidence: 99%

The protein phosphatase-1/inhibitor-2 complex differentially regulates GSK3 dephosphorylation and increases sarcoplasmic/endoplasmic reticulum calcium ATPase 2 levels

King¹,

Gandy²,

Bijur³

2006

Experimental Cell Research

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“…A number of different phosphotransferase activities are altered in brains of AD patients, AD animal models, and cell lines exposed to A␤. The list of abnormal kinase activities in AD is extensive, among them several unrelated serine/threonine protein kinases including GSK3 (23,29,30), p38 (31), JNK (31), cdk5 (32,33), and CK2 (34). Interestingly, many of these enzymes are involved in regulation of FAT (28,29).…”

Section: Oa␤-induced Fat Inhibition Results From Endogenous Ck2 Activmentioning

confidence: 99%

Disruption of fast axonal transport is a pathogenic mechanism for intraneuronal amyloid beta

Pigino

Morfini

Atagi

et al. 2009

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

192

172

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The pathological mechanism by which A␤ causes neuronal dysfunction and death remains largely unknown. Deficiencies in fast axonal transport (FAT) were suggested to play a crucial role in neuronal dysfunction and loss for a diverse set of dying back neuropathologies including Alzheimer's disease (AD), but the molecular basis for pathological changes in FAT were undetermined. Recent findings indicate that soluble intracellular oligomeric A␤ (oA␤) species may play a critical role in AD pathology. Real-time analysis of vesicle mobility in isolated axoplasms perfused with oA␤ showed bidirectional axonal transport inhibition as a consequence of endogenous casein kinase 2 (CK2) activation. Conversely, neither unaggregated amyloid beta nor fibrillar amyloid beta affected FAT. Inhibition of FAT by oA␤ was prevented by two specific pharmacological inhibitors of CK2, as well as by competition with a CK2 substrate peptide. Furthermore, perfusion of axoplasms with active CK2 mimics the inhibitory effects of oA␤ on FAT. Both oA␤ and CK2 treatment of axoplasm led to increased phosphorylation of kinesin-1 light chains and subsequent release of kinesin from its cargoes. Therefore pharmacological modulation of CK2 activity may represent a promising target for therapeutic intervention in AD.Alzheimer's disease ͉ Axonal transport ͉ Beta amyloid oligomer ͉ CK2 ͉ Kinesin T he complex functional changes and histopathology of Alzheimer disease (AD) make it one of the most challenging disorders faced by modern medicine. Histopathological hallmarks of AD include distinctive extracellular and intracellular aggregates of amyloid beta (A␤) and tau (1, 2). Synaptic dysfunction and axonopathy appear to be the earliest lesions in AD as corroborated by reduced immunoreactivity of synaptophysin and other synaptic markers in terminal fields of brain-affected areas (3). AD-affected neurons appear to die eventually as a consequence of synaptic dysfunction and loss, following a typical dying-back pattern of neuronal degeneration.The amyloid hypothesis (4), a dominant concept in AD research for many years, has been revised in recent years to include the notion that smaller soluble A␤ aggregates may play an early and significant role in AD. Soluble oligomers of A␤ (oA␤) have been shown to be neurotoxic both in vivo and in vitro (5-7) as well as altering synaptic structure and function (8). Moreover, oA␤ levels correlate with impairments in cognitive function, learning, and memory (9, 10), but the molecular basis of these effects are uncertain. Intracellular A␤ was first described by Wertkin et al. (11). Immunogold electron microscopy showed that intraneuronal A␤ is pre-and postsynaptically enriched in both AD human brain and AD transgenic animal models in association with dystrophic neurites and abnormal synaptic morphology (12)(13)(14). Spatial and temporal analyses of intraneuronal oA␤ accumulation show that it precedes plaque formation in both AD animal models and Down's syndrome patients, suggesting that oA␤ is an early intracellular toxic agent i...

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“…109 One must be aware, however, that the inhibition of cdk5 was accompanied by activation of GSK-3␤ in neuronal cell culture and that p35 knock-out mice revealed increased GSK-3␤ activity and tau phosphorylation. 110,111 Cdk5 inhibition can be achieved by active site-directed inhibitors, by 2,6,9-trisubstituted purines and aloisines, which are small-molecule inhibitors that interfere with the cdk5/p25 complex formation (Cdk5 inhibitory peptide [CIP]), and by calpain inhibitors, which prevent p25 generation. 101,112,113 The use of active site inhibitors is hampered by their lack of selectivity toward cdk5.…”

Section: Antiphosphorylation Strategiesmentioning

confidence: 99%

Tau-Based Treatment Strategies in Neurodegenerative Diseases

2008

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Summary:Neurofibrillary tangles are a characteristic hallmark of Alzheimer's and other neurodegenerative diseases, such as Pick's disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). These diseases are summarized as tauopathies, because neurofibrillary tangles are composed of intracellular aggregates of the microtubule-associated protein tau. The molecular mechanisms of tau-mediated neurotoxicity are not well understood; however, pathologic hyperphosphorylation and aggregation of tau play a central role in neurodegeneration and neuronal dysfunction. The present review, therefore, focuses on therapeutic approaches that aim to inhibit tau phosphorylation and aggregation or to dissolve preexisting tau aggregates. Further experimental therapy strategies include the enhancement of tau clearance by activation of proteolytic, proteasomal, or autophagosomal degradation pathways or anti-tau directed immunotherapy. Hyperphosphorylated tau does not bind microtubules, leading to microtubule instability and transport impairment. Pharmacological stabilization of microtubule networks might counteract this effect. In several tauopathies there is a shift toward four-repeat tau isoforms, and interference with the splicing machinery to decrease four-repeat splicing might be another therapeutic option.

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A novel CDK5-dependent pathway for regulating GSK3 activity and kinesin-driven motility in neurons

Cited by 247 publications

References 77 publications

The protein phosphatase-1/inhibitor-2 complex differentially regulates GSK3 dephosphorylation and increases sarcoplasmic/endoplasmic reticulum calcium ATPase 2 levels

The protein phosphatase-1/inhibitor-2 complex differentially regulates GSK3 dephosphorylation and increases sarcoplasmic/endoplasmic reticulum calcium ATPase 2 levels

Disruption of fast axonal transport is a pathogenic mechanism for intraneuronal amyloid beta

Tau-Based Treatment Strategies in Neurodegenerative Diseases

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