SRPK2 Phosphorylates Tau and Mediates the Cognitive Defects in Alzheimer's Disease

Yang, Hong; Chan, Chi Bun; Kwon, Il Sun; Li, Xuekun; Song, Mingke; Lee, Hyun Pil; Liu, Xia; Sompol, Pradoldej; Jin, Peng; Lee, Hyoung Gon; Yu, Shan Ping; Ye, Keqiang

doi:10.1523/jneurosci.3300-12.2012

Cited by 54 publications

(59 citation statements)

References 46 publications

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“…In contrast to Srpk1, which is expressed ubiquitously, Srpk2 exhibits particularly high expression levels in the nervous system suggestive of a neuronspecific function (Wang et al 1998). Interestingly, Srpk2 was found to be up-regulated in brains of APP/PS1 transgenic mice, a model for Alzheimer's disease (Hong et al 2012). In that study, knockdown of Srpk2 in APP/PS1 mice alleviated memory deficits and increased synaptic plasticity.…”

Section: Discussionmentioning

confidence: 84%

Subcellular transcriptome alterations in a cell culture model of spinal muscular atrophy point to widespread defects in axonal growth and presynaptic differentiation

Saal

Briese

Kneitz

et al. 2014

RNA

111

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Neuronal function critically depends on coordinated subcellular distribution of mRNAs. Disturbed mRNA processing and axonal transport has been found in spinal muscular atrophy and could be causative for dysfunction and degeneration of motoneurons. Despite the advances made in characterizing the transport mechanisms of several axonal mRNAs, an unbiased approach to identify the axonal repertoire of mRNAs in healthy and degenerating motoneurons has been lacking. Here we used compartmentalized microfluidic chambers to investigate the somatodendritic and axonal mRNA content of cultured motoneurons by microarray analysis. In axons, transcripts related to protein synthesis and energy production were enriched relative to the somatodendritic compartment. Knockdown of Smn, the protein deficient in spinal muscular atrophy, produced a large number of transcript alterations in both compartments. Transcripts related to immune functions, including MHC class I genes, and with roles in RNA splicing were up-regulated in the somatodendritic compartment. On the axonal side, transcripts associated with axon growth and synaptic activity were down-regulated. These alterations provide evidence that subcellular localization of transcripts with axonal functions as well as regulation of specific transcripts with nonautonomous functions is disturbed in Smn-deficient motoneurons, most likely contributing to the pathophysiology of spinal muscular atrophy.

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Section: Discussionmentioning

confidence: 84%

Subcellular transcriptome alterations in a cell culture model of spinal muscular atrophy point to widespread defects in axonal growth and presynaptic differentiation

Saal

Briese

Kneitz

et al. 2014

RNA

111

View full text Add to dashboard Cite

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“…Moreover, both proteins regulate Tau pathological functions via either phosphorylation or cleavage (Hong et al, 2012; Zhang et al, 2014; Zhang et al, 2015). Accordingly, we hypothesize that these two pathways are linked in that SRPK2 might regulate delta-secretase via phosphorylation.…”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, SRPK2 can be activated by Aβ, and activated SRPK2 phosphorylates Tau on S214, suppressing Tau-dependent microtubule polymerization and inhibiting axonal elongation in neurons. SRPK2 activity is augmented in the neurons of Alzheimer’s disease (AD) mice and patients (Hong et al, 2012), strongly implicating a role for SRPK2 in AD disease etiology and pathogenesis. Our previous work also showed that SRPK2 phosphorylates SC35, a SR splicing factor located in nuclear speckles (Jang et al, 2009), and it has recently been reported that dysregulated RNA processing with accumulation of unspliced RNA species occurred in human AD and MCI (mild cognitive impairment) patients (Bai et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Delta-Secretase Phosphorylation by SRPK2 Enhances Its Enzymatic Activity, Provoking Pathogenesis in Alzheimer’s Disease

Wang

Liu

et al. 2017

Molecular Cell

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Summary Delta-secretase, a lysosomal asparagine endopeptidase (AEP), simultaneously cleaves both APP and Tau, controlling the onset of pathogenesis of Alzheimer’s disease (AD). However, how this protease is post-translationally regulated remains unclear. Here we report that Serine-arginine protein kinase 2 (SRPK2) phosphorylates delta-secretase and enhances its enzymatic activity. SRPK2 phosphorylates serine 226 on delta-secretase and accelerates its autocatalytic cleavage, leading to its cytoplasmic translocation and escalated enzymatic activities. Delta-secretase is highly phosphorylated in human AD brains, tightly correlated with SRPK2 activity. Overexpression of phosphorylation mimetic (S226D) in young 3XTg mice strongly promoted APP and Tau fragmentation, and facilitated amyloid plaque deposits and neurofibrillary tangles (NFT) formation, resulting in cognitive impairment. Conversely, viral injection of the non-phosphorylatable mutant (S226A) into 5XFAD mice decreased APP and Tau proteolytic cleavage and attenuated AD pathologies and reversed cognitive defects. Our findings support that delta-secretase phosphorylation by SRPK2 plays a critical role in aggravating AD pathogenesis.

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“…Electrophysiological analysis was carried out as previously described (Hong et al, 2012). Briefly, vehicle-and 7,8-DHFtreated 5XFAD mice were anaesthetized with isoflurane, decapitated, and the hippocampi were cut into 400-mm thick transverse slices with a vibratome.…”

Section: Electrophysiological Analysismentioning

confidence: 99%

7,8-Dihydroxyflavone Prevents Synaptic Loss and Memory Deficits in a Mouse Model of Alzheimer’s Disease

Zhang

Liu

Schroeder

et al. 2013

Neuropsychopharmacol

213

189

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Synaptic loss in the brain correlates well with disease severity in Alzheimer disease (AD). Deficits in brain-derived neurotrophic factor/ tropomyosin-receptor-kinase B (TrkB) signaling contribute to the synaptic dysfunction of AD. We have recently identified 7,8-dihydroxyflavone (7,8-DHF) as a potent TrkB agonist that displays therapeutic efficacy toward various neurological diseases. Here we tested the effect of 7,8-DHF on synaptic function in an AD model both in vitro and in vivo. 7,8-DHF protected primary neurons from Abinduced toxicity and promoted dendrite branching and synaptogenesis. Chronic oral administration of 7,8-DHF activated TrkB signaling and prevented Ab deposition in transgenic mice that coexpress five familial Alzheimer's disease mutations (5XFAD mice). Moreover, 7,8-DHF inhibited the loss of hippocampal synapses, restored synapse number and synaptic plasticity, and prevented memory deficits. These results suggest that 7,8-DHF represents a novel oral bioactive therapeutic agent for treating AD.

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SRPK2 Phosphorylates Tau and Mediates the Cognitive Defects in Alzheimer's Disease

Cited by 54 publications

References 46 publications

Subcellular transcriptome alterations in a cell culture model of spinal muscular atrophy point to widespread defects in axonal growth and presynaptic differentiation

Subcellular transcriptome alterations in a cell culture model of spinal muscular atrophy point to widespread defects in axonal growth and presynaptic differentiation

Delta-Secretase Phosphorylation by SRPK2 Enhances Its Enzymatic Activity, Provoking Pathogenesis in Alzheimer’s Disease

7,8-Dihydroxyflavone Prevents Synaptic Loss and Memory Deficits in a Mouse Model of Alzheimer’s Disease

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