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Translational control by microRNAs is essential for protein homeostatsis in the mouse brain

ABSTRACT: MicroRNAs (miRNAs) are important regulators of gene expression; however, their contribution to protein homeostasis remains unclear. Impaired protein homeostasis could contribute to brain aging and neurodegeneration; however, the underlying mechanisms are not well understood. Here, we show that conditional inactivation of Dicer in the adult mouse brain postnatal forebrain causes age-dependent accumulation of lipofuscin and polyubiquitinated protein aggregates. Impaired protein turnover in the cerebral cortex of Dicer conditional knockout (cKO) mice is associated with protein misfolding and endoplasmic reticulum stress. Conditional Drosha inactivation using the same Cre driver results in similar phenotypes, suggesting that the phenotypes may be due to the loss of canonical miRNAs. RNA-sequencing analysis revealed increased expression of target genes of neocortical neuron-enriched miRNAs in the Dicer cKO neocortex and dysregulated expression of genes involved in protein homeostasis maintenance. Further analysis revealed a similar gene expression profile in the hippocampal CA1 region of Dicer cKO mice as in the aging brain. Moreover, translational inhibition using anisomycin or rapamycin ameliorated the protein aggregation and neurodegeneration in Dicer-deficient brains. Thus, protein translational control by miRNAs is an essential component of the protein homeostasis network controlling neuronal survival in the adult brain. Our results show that excessive translation can produce key features of human neurodegenerative diseases, and suggest that translational suppression may be a therapeutic strategy to restore protein homeostasis and combat neurodegeneration.

ORGANISM(S): Mus musculus

PROVIDER: GSE224423 | GEO | 2023/02/15

REPOSITORIES: GEO

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Project description:The endoribonuclease, Dicer, is indispensible for generating the majority of mature microRNAs (miRNAs), which are posttranscriptional regulators of gene expression involved in a wide range of developmental and pathological processes in mammalian central nervous system. While functions of Dicer-dependent miRNA pathways in neurons and oligodendrocytes have been extensively investigated, little is known about the role of Dicer in astrocytes. Here we report the effect of Cre-loxP mediated conditional deletion of Dicer selectively from postnatal astroglia on brain development. Dicer-deficient mice exhibited normal motor development and neurological morphology prior to postnatal week 5. Thereafter mutant mice invariably developed a rapidly fulminant neurological decline characterized by ataxia, severe progressive cerebellar degeneration, seizures, uncontrollable movements and premature death by postnatal week 9-10. Integrated transcription profiling, histological and functional analyses of cerebella showed that deletion of Dicer in cerebellar astrocytes altered the transcriptome of astrocytes to be more similar to an immature or reactive-like state prior to the onset of neurological symptoms or morphological changes. As a result, critical and mature astrocytic functions including glutamate uptake and antioxidant pathways were substantially impaired, leading to massive apoptosis of cerebellar granule cells and degeneration of Purkinje cells. Collectively, our study demonstrates the critical involvement of Dicer in normal astrocyte maturation and maintenance. Our findings also reveal non-cell autonomous roles of astrocytic Dicer-dependent pathways in regulating proper neuronal functions and implicate that loss of or dysregulation of astrocytic Dicer-dependent pathways may be involved in neurodegeneration and other neurological disorders. Four replicate experiments using samples derived from biologically independent pairs of control (mGfap-Cre; Dicer +/flox) and Dicer mutant (mGfap-Cre; Dicer flox/flox) littermate mice (postnatal day 30) were performed with a dye-swap experimental design.

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Translational control by microRNAs is essential for protein homeostatsis in the mouse brain

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