1. Memory Decline and Its Reversal in Aging and Neurodegeneration Involve miR-183/96/182 Biogenesis.
- Author
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Jawaid A, Woldemichael BT, Kremer EA, Laferriere F, Gaur N, Afroz T, Polymenidou M, and Mansuy IM
- Subjects
- Amyotrophic Lateral Sclerosis genetics, Amyotrophic Lateral Sclerosis pathology, Animals, Cell Line, Tumor, Cell Nucleus metabolism, Cognition Disorders genetics, Cognition Disorders pathology, Frontotemporal Lobar Degeneration genetics, Frontotemporal Lobar Degeneration pathology, Hippocampus metabolism, Hippocampus pathology, Humans, Mice, Inbred C57BL, MicroRNAs genetics, Protein Phosphatase 1 metabolism, RNA-Binding Protein FUS metabolism, Smad Proteins metabolism, Aging pathology, Memory Disorders complications, Memory Disorders genetics, MicroRNAs biosynthesis, Nerve Degeneration complications, Nerve Degeneration genetics
- 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.
- Published
- 2019
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