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Robust RBM3 and β-klotho expression in developing neurons in the human brain.

ABSTRACT: RNA binding motif 3 (RBM3) is a powerful neuroprotectant that inhibits neurodegenerative cell death in vivo and is a promising therapeutic target in brain ischemia. RBM3 is increased by the hormone fibroblast growth factor 21 (FGF21) in an age- and temperature-dependent manner in rat cortical neurons. FGF21 receptor binding is controlled by the transmembrane protein β-klotho, which is mostly absent in the adult brain. We discovered that RBM3/β-klotho is unexpectedly high in the human infant vs. adult brain (hippocampus/prefrontal cortex). The use of tissue homogenates in that study precluded a comparison of RBM3/β-klotho expression among different CNS cell-types, thus, omitted key evidence (i.e. confirmation of neuronal expression) that would otherwise provide a critical link to support their possible direct neuroprotective effects in humans. This report addresses that knowledge gap. High-quality fixed human hippocampus, cortex, and hypothalamic tissues were acquired from the NIH Neurobiobank (<1 yr (premature born) infants, 1 yr, 4 yr, and 34 yr). Dual labeling of cell-type markers vs. RBM3/β-klotho revealed enriched staining of targets in neurons in the developing brain. Identifying that RBM3/β-klotho is abundant in neurons in the immature brain is fundamentally important to guide protocol design and conceptual frameworks germane to future testing of these neuroprotective pathways in humans.

SUBMITTER: Jackson TC

PROVIDER: S-EPMC6890998 | biostudies-literature |

REPOSITORIES: biostudies-literature

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?-Klotho Expression in Human Tissues.

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Klotho inhibits neuronal senescence in human brain organoids.

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Extrarenal α-klotho expression in human tissues

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Klotho inhibits neuronal senescence in human brain organoids

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Extrarenal ?-klotho expression in human tissues

Project description:?-Klotho has emerged as a powerful regulator of the ageing process. To-date, the expression profile of ?-Klotho in human tissues is unknown and its existence in some human tissue types is subject to much controversy. Objective: This is the first study to characterize system-wide tissue expression of transmembrane ?-Klotho in humans. We have employed next generation targeted proteomic analysis using Parallel Reaction Monitoring (PRM) in parallel with conventional antibody-based methods to determine the expression and spatial distribution of human ?-Klotho expression in health. Results: The distribution of ?-Klotho in human tissues from various organ systems, including arterial, epithelial, endocrine, reproductive and neuronal tissues was first identified by immunohistochemistry. Kidney tissues showed strong ?-Klotho expression, while liver did not reveal a detectable signal. These results were next confirmed by western blotting of both whole tissues and primary cells. To validate our antibody-based results, ?-Klotho expressing tissues were subjected to PRM mass spectrometry identifying peptides specific for the full length, transmembrane ?-Klotho isoform. Conclusions: The data presented confirms ?-Klotho expression in the kidney tubule and in artery, and provides evidence of ?-Klotho expression across organ systems and cell-types that have not previously been described in humans.

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