Knockout of the longevity gene Klotho perturbs aging and Alzheimer's disease-linked brain microRNAs and tRNA fragments.

Document Type

Article

Abstract

Overexpression of the longevity gene Klotho prolongs lifespan, while its knockout shortens lifespan and impairs cognition via perturbation of myelination and synapse formation. However, comprehensive analysis of Klotho knockout effects on mammalian brain transcriptomics is lacking. Here, we report that Klotho knockout alters the levels of aging- and cognition related mRNAs, long non-coding RNAs, microRNAs and tRNA fragments. These include altered neuronal and glial regulators in murine models of aging and Alzheimer's disease and in human Alzheimer's disease post-mortem brains. We further demonstrate interaction of the knockout-elevated tRNA fragments with the spliceosome, possibly affecting RNA processing. Last, we present cell type-specific short RNA-seq datasets from FACS-sorted neurons and microglia of live human brain tissue demonstrating in-depth cell-type association of Klotho knockout-perturbed microRNAs. Together, our findings reveal multiple RNA transcripts in both neurons and glia from murine and human brain that are perturbed in Klotho deficiency and are aging- and neurodegeneration-related.

Keywords

Klotho Proteins, MicroRNAs, Animals, Aging, Alzheimer Disease, Brain, Mice, Glucuronidase, Humans, Longevity, Mice, Knockout, RNA, Transfer, Male, Neurons, Mice, Inbred C57BL

Medical Subject Headings

Klotho Proteins; MicroRNAs; Animals; Aging; Alzheimer Disease; Brain; Mice; Glucuronidase; Humans; Longevity; Mice, Knockout; RNA, Transfer; Male; Neurons; Mice, Inbred C57BL

Publication Date

6-11-2024

Publication Title

Commun Biol

ISSN

2399-3642

Volume

7

Issue

1

First Page

720

Last Page

720

PubMed ID

38862813

Digital Object Identifier (DOI)

10.1038/s42003-024-06407-y

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