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

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. Bulk RNAseq based transcriptomic analyses of mouse necortex and mouse hipocampal CA1 region samples with Dicer conditional knockout and control samples