Truncation and Activation of Dual Specificity Tyrosine Phosphorylation-regulated Kinase 1A by Calpain I

Jin, Nana; Yin, Xiaomin; Gu, Jianlan; Zhang, Xinhua; Shi, Jing; Qian, Wei; Ji, Yuhua; Cao, Mei; Gu, Xiaosong; Ding, Fei; Iqbal, Khalid; Chen, Gong; Liu, Fei

doi:10.1074/jbc.m115.645507

Cited by 51 publications

(62 citation statements)

References 90 publications

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“…Dysregulation of alternative splicing of Tau has been reported in DS as well as in AD [37] and may also underlie the abnormal hyper-phosphorylation of Tau [38]. Furthermore, two genes located on Chromosome 21, the dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) gene, and regulator of calcineurin 1 (RCAN1), are highly expressed in the DS brain [39–41], and have been implicated in the dysregulation of Tau phosphorylation associated with early onset AD in DS [42, 43, 44]. Taken together, dysregulation of these genes suggest several alternative molecular mechanisms underlying the increase in Aβ 1-42 , P-S396-Tau and P-T181-Tau observed in neuronal exosomes isolated from children with DS, which will be further explored in ongoing expanded studies.…”

Section: Discussionmentioning

confidence: 99%

Neuronal exosomes reveal Alzheimer's disease biomarkers in Down syndrome

Hamlett

Goetzl

Ledreux

et al. 2016

Alzheimer's & Dementia

104

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INTRODUCTION Individuals with Down syndrome (DS) exhibit Alzheimer’s disease (AD) neuropathology and dementia early in life. Blood biomarkers of AD neuropathology would be valuable, as non-AD intellectual disabilities of DS and AD dementia overlap clinically. We hypothesized that elevations of amyloid-beta (Aβ) peptides and phosphorylated-Tau (P-Tau) in neuronal exosomes may document preclinical AD. METHODS AD neuropathogenic proteins Aβ1-42, P-T181-Tau and P-S396-Tau were quantified by enzyme-linked immunosorbent assays in extracts of neuronal exosomes purified from blood of individuals with DS and age-matched controls. RESULTS Neuronal exosome levels of Aβ1-42, P-T181-Tau and P-S396-Tau were significantly elevated in individuals with DS compared to age-matched controls at an early age. No significant gender differences were observed. DISCUSSION These early increases in Aβ1-42, P-T181-Tau, and P-S396-Tau in individuals with DS may provide a basis for early intervention as targeted treatments become available.

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Section: Discussionmentioning

confidence: 99%

Neuronal exosomes reveal Alzheimer's disease biomarkers in Down syndrome

Hamlett

Goetzl

Ledreux

et al. 2016

Alzheimer's & Dementia

104

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“…Calpain I proteolyzes Dyrk1A at the C-terminus and enhances its kinase activity toward to tau in vitro 32 . In AD brain, truncation of Dyrk1A is positively correlated with the 3R-tau/4R-tau ratio.…”

Section: Discussionmentioning

confidence: 99%

Dyrk1A overexpression leads to increase of 3R-tau expression and cognitive deficits in Ts65Dn Down syndrome mice

Yin

Jin

Shi

et al. 2017

Sci Rep

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Alternative splicing of tau exon 10 generates tau isoforms with three or four microtubule-binding repeats, 3R-tau and 4R-tau, which is equally expressed in adult human brain. Imbalanced expression in 3R-tau and 4R-tau has been found in several sporadic and inherited tauopathies, suggesting that dysregulation of tau exon 10 is sufficient to cause neurodegenerative diseases. We previously reported that Dyrk1A, which is overexpressed in Down syndrome brains, regulates alternative splicing of exogenous tau exon 10. In the present study, we investigated the regulation of endogenous tau exon 10 splicing by Dyrk1A. We found that inhibition of Dyrk1A enhanced tau exon 10 inclusion, leading to an increase in 4R-tau/3R-tau ratio in differentiated-human neuronal progenitors and in the neonatal rat brains. Accompanied with overexpression of Dyrk1A, 3R-tau was increased and 4R-tau was decreased in the neonatal brains of Ts65Dn mice, a model of Down syndrome. Treatment with Dyrk1A inhibitor, green tea flavonol epigallocatechin-gallate (EGCG), from gestation to adulthood suppressed 3R-tau expression and rescued anxiety and memory deficits in Ts65Dn mouse brains. Thus, Dyrk1A might be an ideal therapeutic target for Alzheimer’s disease, especially for Down syndrome and EGCG which inhibits Dyrk1A may have potential effect on the treatment or prevention of this disease.

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“…However, increasing Ser9 phosphorylation by inhibiting certain phosphatases, such as phosphatase 1/2A prevented calpain-mediated cleavage of GSK-3β [68], indicating that the relationship between calpain, GSK-3β and tau hyperphosphorylation is extremely complex. Furthermore, another protein kinase, dual specificity tyrosine-phosphorylation-regulated kinase 1A (Dyrk1A), has been shown to exhibit enhanced activity towards tau phosphorylation as a result of calpain-mediated cleavage [70]. Finally, down-regulation of calpastatin enhanced tau neurotoxicity, an effect that is abolished by overexpression of calpastatin [71].…”

Section: Opposite Roles Of Calpain-1 and Calpain-2 In Neuroprotectionmentioning

confidence: 99%

Calpain-1 and Calpain-2: The Yin and Yang of Synaptic Plasticity and Neurodegeneration

Baudry

2016

Trends in Neurosciences

188

173

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Many signaling pathways participate in both synaptic plasticity and neuronal degeneration. While calpains participate in these phenomena, very few studies have evaluated the respective roles of the two major calpain isoforms in the brain, calpain-1 and calpain-2. We review recent studies indicating that calpain-1 and calpain-2 exhibit opposite functions in both synaptic plasticity and neurodegeneration. Calpain-1 activation is required for the induction of long-term potentiation (LTP) and is generally neuroprotective, while calpain-2 activation limits the extent of potentiation and is neurodegenerative. This duality of functions is related to their associations with different PDZ binding proteins, resulting in differential subcellular localization, and offers new therapeutic opportunities for a number of indications in which these proteases have previously been implicated.

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Truncation and Activation of Dual Specificity Tyrosine Phosphorylation-regulated Kinase 1A by Calpain I

Cited by 51 publications

References 90 publications

Neuronal exosomes reveal Alzheimer's disease biomarkers in Down syndrome

Neuronal exosomes reveal Alzheimer's disease biomarkers in Down syndrome

Dyrk1A overexpression leads to increase of 3R-tau expression and cognitive deficits in Ts65Dn Down syndrome mice

Calpain-1 and Calpain-2: The Yin and Yang of Synaptic Plasticity and Neurodegeneration

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