CLSPCOL rescues Alzheimer's disease mouse models.

Calmodulin-like skin protein (CLSP) inhibits Alzheimer's disease (AD)-related neurotoxicity. The activity of CLSP is reduced in AD. To restore the CLSP activity, we developed a hybrid peptide named CLSPCOL, consisting of CLSP(1-61) and the collagen-homologous region (COL) of adiponectin.

Proline-arginine poly-dipeptide encoded by the C9orf72 repeat expansion inhibits adenosine deaminase acting on RNA.

A GGGGCC hexanucleotide repeat expansion in the C9orf72 gene is linked to the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9-ALS/FTD). Unconventional translation of the hexanucleotide repeat expansion generates five dipeptide repeat proteins (DPRs). The molecular mechanism underlying the DPR-linked neurotoxicity is under investigation.

Identification of highest neurotoxic amyloid-β plaque type showing reduced contact with astrocytes.

Amyloid-β (Aβ) plaques are strongly associated with the development of Alzheimer's disease (AD). However, it remains unclear how morphological differences in Aβ plaques determine the pathogenesis of Aβ. Here, we categorized Aβ plaques into four types based on the macroscopic features of the dense core, and found that the Aβ-plaque subtype containing a larger dense core showed the strongest association with neuritic dystrophy.

Mitochondrial ubiquitin ligase alleviates Alzheimer's disease pathology via blocking the toxic amyloid-β oligomer generation.

Mitochondrial pathophysiology is implicated in the development of Alzheimer's disease (AD). An integrative database of gene dysregulation suggests that the mitochondrial ubiquitin ligase MITOL/MARCH5, a fine-tuner of mitochondrial dynamics and functions, is downregulated in patients with AD. Here, we report that the perturbation of mitochondrial dynamics by MITOL deletion triggers mitochondrial impairments and exacerbates cognitive decline in a mouse model with AD-related Aβ pathology.

Restoration of the reduced CLSP activity alleviates memory impairment in Alzheimer disease.

Calmodulin-like skin protein (CLSP), a secreted peptide, inhibits neuronal death in cell-based Alzheimer's disease (AD) models and transgenic overexpression of the CLSP gene suppresses synaptic loss and memory impairment in AD model mice, APPswe/PS1dE9 double transgenic mice (APP/PS1 mice). Despite the anticipated role of CLSP as an AD-suppressing factor, it remains unanswered whether the insufficiency of the CLSP activity is linked to the AD pathogenesis. In this study, we first show that adiponectin, a CLSP potentiator/protector, dominantly determines the CLSP activity in the central nervous system where there are sufficient concentrations of CLSP, higher concentrations of CLSP inhibitors such as apolipoprotein E, and smaller concentrations of adiponectin.

[Practical training of pharmacokinetics with an web-based simulation application].

A computer simulation application on pharmacokinetics, which we developed using a software, named "Stella", has been successfully used for the virtual training of pharmacokinetics at multiple medical schools. The training course using Stella has encouraged the medical students to optimize drug administration for individual patients on the computers. Importantly, the virtual training is free of any concern on human and animal ethics.

C9-ALS/FTD-linked proline-arginine dipeptide repeat protein associates with paraspeckle components and increases paraspeckle formation.

A GGGGCC hexanucleotide repeat expansion in the C9ORF72 gene has been identified as the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. The repeat expansion undergoes unconventional translation to produce five dipeptide repeat proteins (DPRs). Although DPRs are thought to be neurotoxic, the molecular mechanism underlying the DPR-caused neurotoxicity has not been fully elucidated.

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

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.

The proline-arginine repeat protein linked to C9-ALS/FTD causes neuronal toxicity by inhibiting the DEAD-box RNA helicase-mediated ribosome biogenesis.

A GGGGCC repeat expansion in the C9ORF72 gene has been identified as the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. The repeat expansion undergoes unconventional translation to produce dipeptide repeat (DPR) proteins. Although it has been reported that DPR proteins cause neurotoxicity, the underlying mechanism has not been fully elucidated.

Calmodulin-like skin protein protects against spatial learning impairment in a mouse model of Alzheimer disease.

Humanin and calmodulin-like skin protein (CLSP) inhibits Alzheimer disease (AD)-related neuronal cell death via the heterotrimeric humanin receptor in vitro. It has been suggested that CLSP is a central agonist of the heterotrimeric humanin receptor in vivo. To investigate the role of CLSP in the AD pathogenesis in vivo, we generated mouse CLSP-1 transgenic mice, crossed them with the APPswe/PSEN1dE9 mice, a model mouse of AD, and examined the effect of CLSP over-expression on the pathological phenotype of the AD mouse model.

Calmodulin-like skin protein is downregulated in human cerebrospinal fluids of Alzheimer's disease patients with apolipoprotein E4; a pilot study using postmortem samples.

Objective: Calmodulin-like skin protein (CLSP) is a secreted peptide that inhibits neuronal cell death, linked to Alzheimer's disease (AD), by binding to the heterotrimeric humanin receptor and activating an intracellular survival pathway. CLSP is only expressed in skin keratinocytes and related epithelial cells, circulates in the blood stream, and passes the blood-cerebrospinal fluid (CSF) barrier. In the current study, we addressed the issues as to whether CLSP functions in the central nervous system and whether the concentration of CLSP is reduced in the CSFs of AD patients.

hnRNPA1 autoregulates its own mRNA expression to remain non-cytotoxic.

Heterogeneous nuclear ribonucleoprotein (hnRNP)A1, a member of the hnRNP family, is involved in a variety of RNA metabolisms. The hnRNPA1 expression is altered in some human diseases and mutations of the hnRNPA1 gene cause amyotrophic lateral sclerosis and multisystem proteinopathy. It has been therefore assumed that the dysregulation of hnRNPA1 is linked to the pathogenesis of the diseases.

The Lysosomal Trafficking Transmembrane Protein 106B Is Linked to Cell Death.

A common genetic variation in the transmembrane protein 106B (TMEM106B) gene has been suggested to be a risk factor for frontotemporal lobar degeneration (FTLD) with inclusions of transactive response DNA-binding protein-43 (TDP-43) (FTLD-TDP), the most common pathological subtype in FTLD. Furthermore, previous studies have shown that TMEM106B levels are up-regulated in the brains of FTLD-TDP patients, although the significance of this finding remains unknown. In this study, we show that the overexpression of TMEM106B and its N-terminal fragments induces cell death, enhances oxidative stress-induced cytotoxicity, and causes the cleavage of TDP-43, which represents TDP-43 pathology, using cell-based models.

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

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 wild-type UNC5C causes low-grade death, which is intensified by an AD-linked mutation T835M.

Glycolytic flux controls D-serine synthesis through glyceraldehyde-3-phosphate dehydrogenase in astrocytes.

D-Serine is an essential coagonist with glutamate for stimulation of N-methyl-D-aspartate (NMDA) glutamate receptors. Although astrocytic metabolic processes are known to regulate synaptic glutamate levels, mechanisms that control D-serine levels are not well defined. Here we show that d-serine production in astrocytes is modulated by the interaction between the D-serine synthetic enzyme serine racemase (SRR) and a glycolytic enzyme, glyceraldehyde 3-phosphate dehydrogenase (GAPDH).

Nuclear TDP-43 causes neuronal toxicity by escaping from the inhibitory regulation by hnRNPs.

Dysregulation of transactive response DNA-binding protein-43 (TDP-43) is thought to be linked to the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). TDP-43 normally localizes in the nucleus but its main localization shifts to the cytoplasm in most affected cells of ALS and FTLD patients. It is not yet known whether nuclear or cytoplasmic TDP-43 is responsible for TDP-43-induced neurotoxicity.

Apollon/Bruce is upregulated by Humanin.

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.

Protective effects of Humanin and calmodulin-like skin protein in Alzheimer's disease and broad range of abnormalities.

Humanin is a 24-amino acid, secreted bioactive peptide that prevents various types of cell death and improves some types of cell dysfunction. Humanin inhibits neuronal cell death that is caused by a familial Alzheimer's disease (AD)-linked gene via binding to the heterotrimeric Humanin receptor (htHNR). This suggests that Humanin may play a protective role in AD-related pathogenesis.

A mutation protective against Alzheimer's disease renders amyloid β precursor protein incapable of mediating neurotoxicity.

Expression of a familial Alzheimer's disease (AD)-linked mutant of amyloid β precursor protein (APP) or the binding of transforming growth factor β2 to wild-type (wt)-APP causes neuronal death by activating an intracellular death signal (a APP-mediated intracellular death signal) in the absence of the involvement of amyloid β (Aβ) toxicity in vitro. These neuronal death models may therefore be regarded as Aβ-independent neuronal death models related to AD. A recent study has shown that the A673T mutation in the APP isoform APP770 , corresponding to the A598T mutation in the most prevalent neuronal APP isoform APP695 (an AD-protective mutant of APP), is linked to a reduction in the incidence rate of AD.

KCTD20, a relative of BTBD10, is a positive regulator of Akt.

Background: BTBD10 binds to Akt and protein phosphatase 2A (PP2A) and inhibits the PP2A-mediated dephosphorylation of Akt, thereby keeping Akt activated. Previous studies have suggested that BTBD10 plays an important role in preventing motor neuronal death and accelerating the growth of pancreatic beta cells. Because levels of BTBD10 expression are much lower in many non-nervous tissues than nervous tissues, there may be a relative of BTBD10 that has BTBD10-like function in non-neuronal cells.

SH3-binding protein 5 mediates the neuroprotective effect of the secreted bioactive peptide humanin by inhibiting c-Jun NH2-terminal kinase.

Humanin is a secreted bioactive peptide that suppresses cell toxicity caused by a variety of insults. The neuroprotective effect of Humanin against Alzheimer disease (AD)-related death is mediated by the binding of Humanin to its heterotrimeric Humanin receptor composed of ciliary neurotrophic receptor α, WSX-1, and gp130, as well as the activation of intracellular signaling pathways including a JAK2 and STAT3 signaling axis. Despite the elucidation of the signaling pathways by which Humanin mediates its neuroprotection, the transcriptional targets of Humanin that behaves as effectors of Humanin remains undefined.

Secreted calmodulin-like skin protein ameliorates scopolamine-induced memory impairment.

Humanin, a short bioactive peptide, inhibits cell death in a variety of cell-based death models through Humanin receptors in vitro. In vivo, Humanin ameliorates both muscarinic receptor antagonist-induced memory impairment in normal mice and memory impairment in Alzheimer's disease (AD)-relevant mouse models including aged transgenic mice expressing a familial AD-linked gene. Recently, calmodulin-like skin protein (CLSP) has been shown to be secreted from skin tissues, contain a region minimally similar to the core region of Humanin, and inhibit AD-related neuronal death through the heterotrimeric Humanin receptor on the cell surface in vitro.

Reduced expression of BTBD10 in anterior horn cells with Golgi fragmentation and pTDP-43-positive inclusions in patients with sporadic amyotrophic lateral sclerosis.

Overexpression of BTBD10 (BTB/POZ domain-containing protein 10) suppresses G93A-superoxide dismutase 1 (SOD1)-induced motor neuron death in a cell-based amyotrophic lateral sclerosis (ALS) model. In the present study, paraffin sections of spinal cords from 13 patients with sporadic ALS and 10 with non-ALS disorders were immunostained using a polyclonal anti-BTBD10 antibody. Reduced BTBD10 expression in the anterior horn cells was more frequent in spinal cords from ALS patients than in cords from patients with non-ALS disorders.