Secreted calmodulin-like skin protein inhibits neuronal death in cell-based Alzheimer’s disease models via the heterotrimeric Humanin receptor

Hashimoto, Yuichi; Nawa, Mikiro; Kurita, Megumi; Tokizawa, Mutsutomo; Iwamatsu, Akihiro; Matsuoka, Masao

doi:10.1038/cddis.2013.80

Cited by 25 publications

(46 citation statements)

References 46 publications

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“…CLSP inhibits both the APP-mediated neuronal cell death (21,24) and the UNC5C-mediated neuronal cell death (Fig. 2).…”

Section: Discussionmentioning

confidence: 99%

“…Purified GST-mCLSP1-MycHis, bound to Glutathione-Sepharose (GE Healthcare), was co-incubated in PBS containing thrombin (1 unit/ml, GE Healthcare) at 25°C overnight to be released from GST that bound to the glutathione-Sepharose, as shown previously (21). Recombinant GST protein was also purified for the usage as a negative control.…”

Section: Methodsmentioning

confidence: 99%

“…Cells, Cell Death, and Cell Viability-Neuronal cell death assays related to AD were first performed by Yamatsuji et al (10) and previously described in detail (11)(12)(13)21). Neurohybrid F11 cells were also described earlier (22).…”

Section: Methodsmentioning

confidence: 99%

“…BSA (Sigma) or GST was used as negative controls. At 72 h after the onset of the transfection, the cells were harvested for the cell viability assays using the WST-8 cell death assay kit (Dojindo, Kumamoto, Japan) or staining with calcein AM (Dojindo), and trypan blue exclusion death assays with their microscopic views taken to show viable cells that were attached to cell plates, as described previously (13,21,23).…”

Section: Methodsmentioning

confidence: 99%

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An Alzheimer Disease-linked Rare Mutation Potentiates Netrin Receptor Uncoordinated-5C-induced Signaling That Merges with Amyloid β Precursor Protein Signaling

Hashimoto¹,

Toyama²,

Kusakari³

et al. 2016

Journal of Biological Chemistry

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A missense mutation (T835M) in the uncoordinated-5C (UNC5C) netrin receptor gene increases the risk of late-onset Alzheimer disease (AD) and also the vulnerability of neurons harboring the mutation to various insults. The molecular mechanisms underlying T835M-UNC5C-induced death remain to be elucidated. In this study, we show that overexpression of wildtype UNC5C causes low-grade death, which is intensified by an AD-linked mutation T835M. An AD-linked survival factor, calmodulin-like skin protein (CLSP), and a natural ligand of UNC5C, netrin1, inhibit this death. T835M-UNC5C-induced neuronal cell death is mediated by an intracellular death-signaling cascade, consisting of death-associated protein kinase 1/protein kinase D/apoptosis signal-regulating kinase 1 (ASK1)/ JNK/NADPH oxidase/caspases, which merges at ASK1 with a death-signaling cascade, mediated by amyloid ␤ precursor protein (APP). Notably, netrin1 also binds to APP and partially inhibits the death-signaling cascade, induced by APP. These results may provide new insight into the amyloid ␤-independent pathomechanism of AD.

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“…CLSP inhibits both the APP-mediated neuronal cell death (21,24) and the UNC5C-mediated neuronal cell death (Fig. 2).…”

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

An Alzheimer Disease-linked Rare Mutation Potentiates Netrin Receptor Uncoordinated-5C-induced Signaling That Merges with Amyloid β Precursor Protein Signaling

Hashimoto¹,

Toyama²,

Kusakari³

et al. 2016

Journal of Biological Chemistry

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“…This inhibitory effect is mediated via binding of Humanin to its heterotrimeric receptor (htHNR), which is composed of gp130, ciliary neurotrophic factor receptor a, and WSX-1 [5]. A recent study showed that secreted calmodulin-like skin protein (CLSP) is a physiological agonist of the htHNR that is 10 5 fold more potent than Humanin and suggested that CLSP, rather than Humanin, plays a central role in inhibiting neuronal cell death in vivo [6].…”

Section: Introductionmentioning

confidence: 98%

Apollon/Bruce is upregulated by Humanin

et al. 2014

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Humanin, a short bioactive peptide, inhibits a variety of cell deaths. Humanin-mediated inhibition of neuronal cell death, caused by an Alzheimer's disease (AD)-linked mutant gene occurs via binding of Humanin to its heterotrimeric Humanin receptor (htHNR), which results in the activation of the Janus-associated kinases (JAKs) and signal transducer and activator and transcription 3 (STAT3) signaling pathway. A previous study demonstrated that the Humanin-induced activation of the htHNR/JAK2/STAT3 signaling pathway leads to increased expression of SH3 domain-binding protein 5 (SH3BP5), which is an essential effector of Humanin's anti-cell death activity in some cultured neuronal cells. However, it remains unknown whether SH3BP5 is the sole effector of the Humanin signaling pathway via htHNR/JAKs/STAT3. Here we show that the Humanin signaling pathway via htHNR/JAKs/STAT3 increased the expression levels of mRNA and protein of Apollon/Bruce, an unusual member of the inhibitors of apoptosis proteins, and that overexpression of Apollon/Bruce inhibits neuronal death, caused by a London-type familial AD-linked mutant (V642I) of amyloid β precursor protein. Overall, the results indicate that expression of Apollon/Bruce is upregulated by Humanin, and Apollon/Bruce could be an effector of Humanin in a context-dependent manner.

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Calmodulin‐like skin protein suppresses the increase in senescence‐associated β‐galactosidase induced by hydrogen peroxide or ultraviolet irradiation in keratinocytes

Yusuke

Miyachi

Nawa

et al. 2019

Cell Biology International

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Calmodulin‐like skin protein (CLSP) is a secreted peptide that is produced by skin keratinocytes and some related epithelial cells. It has previously been shown that CLSP is recruited via the bloodstream into the central nervous system where it likely exerts a neuroprotective effect against toxicity related to Alzheimer's disease (AD) by binding to the heterotrimeric humanin receptor and activating intracellular survival signaling. However, it remains to be elucidated whether secreted CLSP shows a protective effect in the skin tissues. In the current study, using primary keratinocytes treated with hydrogen peroxide (H2O2) or exposed to ultraviolet (UV) irradiation as senescence models of keratinocytes, we addressed whether CLSP affects senescence in skin keratinocytes. We found that CLSP expression was upregulated by H2O2 or UV in keratinocytes. Furthermore, co‐incubation with recombinant CLSP reduced the increase in senescence‐associated β‐galactosidase‐positivity in keratinocytes that were induced by H2O2 or UV. These results suggest that CLSP may function as a senescence‐suppressing factor in keratinocytes.

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Secreted calmodulin-like skin protein inhibits neuronal death in cell-based Alzheimer’s disease models via the heterotrimeric Humanin receptor

Cited by 25 publications

References 46 publications

An Alzheimer Disease-linked Rare Mutation Potentiates Netrin Receptor Uncoordinated-5C-induced Signaling That Merges with Amyloid β Precursor Protein Signaling

An Alzheimer Disease-linked Rare Mutation Potentiates Netrin Receptor Uncoordinated-5C-induced Signaling That Merges with Amyloid β Precursor Protein Signaling

Apollon/Bruce is upregulated by Humanin

Calmodulin‐like skin protein suppresses the increase in senescence‐associated β‐galactosidase induced by hydrogen peroxide or ultraviolet irradiation in keratinocytes

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