Rapid and Robust Multi-Phenotypic Assay System for ALS Using Human iPS Cells with Mutations in Causative Genes.

Amyotrophic lateral sclerosis (ALS) is a major life-threatening disease caused by motor neuron degeneration. More effective treatments through drug discovery are urgently needed. Here, we established an effective high-throughput screening system using induced pluripotent stem cells (iPSCs).

Identification of calcium and integrin-binding protein 1 as a novel regulator of production of amyloid β peptide using CRISPR/Cas9-based screening system.

The aberrant metabolism of amyloid β peptide (Aβ) has been implicated in the etiology of Alzheimer disease (AD). Aβ is produced via the sequential cleavage of amyloid precursor protein (APP) by β- and γ-secretases. However, the precise regulatory mechanism of Aβ generation still remains unclear.

Retrograde transport of γ-secretase from endosomes to the trans-Golgi network regulates Aβ42 production.

Unlabelled: The aberrant metabolism of amyloid-β protein (Aβ) in the human brain has been implicated in the etiology of Alzheimer disease (AD). γ-Secretase is the enzyme that generates various forms of Aβ, such as Aβ40 and Aβ42, the latter being an aggregation-prone toxic peptide that is involved in the pathogenesis of AD. Recently, we found that clathrin-mediated endocytosis of γ-secretase affects the production and deposition of Aβ42 in vivo, suggesting that the membrane trafficking of γ-secretase affects its enzymatic activity.

BIN1 regulates BACE1 intracellular trafficking and amyloid-β production.

BIN1 is a genetic risk factor of late-onset Alzheimer disease (AD), which was identified in multiple genome-wide association studies. BIN1 is a member of the amphiphysin family of proteins, and contains N-terminal Bin-Amphiphysin-Rvs and C-terminal Src homology 3 domains. BIN1 is widely expressed in the mouse and human brains, and has been reported to function in the endocytosis and the endosomal sorting of membrane proteins.

FTY720/fingolimod, a sphingosine analogue, reduces amyloid-β production in neurons.

Sphingosine-1-phosphate (S1P) is a pluripotent lipophilic mediator working as a ligand for G-protein coupled S1P receptors (S1PR), which is currently highlighted as a therapeutic target for autoimmune diseases including relapsing forms of multiple sclerosis. Sphingosine related compounds, FTY720 and KRP203 known as S1PR modulators, are phosphorylated by sphingosine kinase 2 (SphK2) to yield the active metabolites FTY720-P and KRP203-P, which work as functional antagonists for S1PRs. Here we report that FTY720 and KRP203 decreased production of Amyloid-β peptide (Aβ), a pathogenic proteins causative for Alzheimer disease (AD), in cultured neuronal cells.