Memory Decline and Its Reversal in Aging and Neurodegeneration Involve miR-183/96/182 Biogenesis

Abstract

Aging is characterized by progressive memory decline that can lead to dementia when associated with neurodegeneration. Here, we show in mice that aging-related memory decline involves defective biogenesis of microRNAs (miRNAs), in particular miR-183/96/182 cluster, resulting from increased protein phosphatase 1 (PP1) and altered receptor SMAD (R-SMAD) signaling. Correction of the defect by miR-183/96/182 overexpression in hippocampus or by environmental enrichment that normalizes PP1 activity restores memory in aged animals. Regulation of miR-183/96/182 biogenesis is shown to involve the neurodegeneration-related RNA-binding proteins TDP-43 and FUS. Similar alterations in miR-183/96/182, PP1, and R-SMADs are observed in the brains of patients with amyotrophic lateral sclerosis (ALS) or frontotemporal lobar degeneration (FTLD), two neurodegenerative diseases with pathological aggregation of TDP-43. Overall, these results identify new mechanistic links between miR-183/96/182, PP1, TDP-43, and FUS in age-related memory deficits and their reversal.

Muscarinic-Dependent miR-182 and QR2 Expression Regulation in the Anterior Insula Enables Novel Taste Learning

“…Intriguingly, previous studies have demonstrated the suppression of miR-182 cluster by protein phosphatase 1 (PP1) as a removable constraint on memory formation (Genoux et al, 2002;. The authors describe the reduced expression of miR-182 and the associated cognitive decline as reversible by overexpression of the miR-182 cluster (Jawaid et al, 2019), which is underexpressed during aberrant PP1 activity in aging and neurodegeneration. It is therefore possible that QR2 is placed further downstream as part of the effect of PP1-mediated miR-182 regulation following novel taste stimulus in the aIC (Adaikkan and Rosenblum, 2012).…”

Characterising the Transcriptional and Translational Impact of the Schizophrenia-Associated miR-1271-5p in Neuronal Cells

“…For example, miR-96-5p expression has been associated with the coordination of neural crest [49] and auditory hindbrain development [50], as well as the induction and progression of neuronal differentiation [51][52][53]. It has also been shown to be involved in the regulation of long-term memory [54,55] and pain sensitivity [56]. Furthermore, mutations in the miR-96-5p seed region have been linked to progressive hearing loss due to defects in the cochlear hair cells [57,58].…”

Friend or foe—Post-translational modifications as regulators of phase separation and RNP granule dynamics

“…Interestingly, both Tau and TDP-43 can be phosphorylated by Tau tubulin kinases 1 and 2 (TTBK1/2) (97,133), and elevated levels of TTBK1/2 have been identified in brains of AD (134) as well as FTD-Tau and FTD-TDP patients (98), where they co-localize with pTDP-43 (97). A phosphatase that was found to be elevated in the aging brain and cortices of ALS patients is the nuclear PP1 isoform PP1␥ (158), furthermore indicating that misregulated phosphorylation and dephosphorylation events may contribute to pathological protein aggregation and neurodegeneration.…”