MicroRNA-335-5p modulates spatial memory and hippocampal synaptic plasticity

Capitano, Fabrizio; Camon, Jeremy; Licursi, Valerio; Ferretti, Valentina; Maggi, Laura; Scianni, Maria; Vecchio, Giorgio Del; Rinaldi, Arianna; Mannironi, Cecilia; Limatola, Cristina; Presutti, Carlo; Mele, Andrea

doi:10.1016/j.nlm.2016.12.019

Cited by 29 publications

(21 citation statements)

References 35 publications

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“…Our results in ALS patients add evidence to a possible role of this specific non-coding RNA in the pathogenic process of motor neuron degeneration. It has been reported that miR335-5p downregulation is necessary to stabilize plasticity and memory in mice 31 and may play a role in the appearance of cognitive symptoms in ALS patients with concomitant FTD, thus theoretically, contributing to the whole clinical spectrum of the disease.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of miR-335-5P in Amyotrophic Lateral Sclerosis Can Contribute to Neuronal Mitochondrial Dysfunction and Apoptosis

Luna

Turon-Sans

Cortés-Vicente

et al. 2020

Sci Rep

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease for which the pathophysiological mechanisms of motor neuron loss are not precisely clarified. Environmental and epigenetic mechanisms such as microRNAs (miRNAs) could have a role in disease progression. We studied the expression pattern of miRNAs in ALS serum from 60 patients and 29 healthy controls. We also analyzed how deregulated miRNAs found in serum affected cellular pathways such as apoptosis, autophagy and mitochondrial physiology in SH-SY5Y cells. We found that miR-335-5p was downregulated in ALS serum. SH-SY5Y cells were transfected with a specific inhibitor of miR-335-5p and showed abnormal mitochondrial morphology, with an increment of reactive species of oxygen and superoxide dismutase activity. Pro-apoptotic caspases-3 and 7 also showed an increased activity in transfected cells. The downregulation of miR-335-5p, which has an effect on mitophagy, autophagy and apoptosis in SH-SY5Y neuronal cells could have a role in the motor neuron loss observed in ALS. Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease. It is classically characterized by weakness and atrophy due to loss of lower motor neurons in the brainstem and spinal cord and loss of upper motor neurons in the motor cortex 1. Degeneration, however, is now considered to be more widespread and not restricted to the motor system. Up to 50% of patients show evidence of behavioral and cognitive dysfunction, suggesting pathologic changes involving the frontal and temporal cortex, and sometimes fulfilling diagnostic criteria of frontotemporal dementia (FTD). These disorders are now considered to be manifestations within the clinicopathological spectrum of an underlying mechanism of neurodegeneration 2,3. The molecular pathogenic mechanism of ALS onset and progression is not completely known. Environmental factors have been described as potential contributors to neurodegeneration and ALS progression, but none have proven to be causative 4,5. Mutations in more than 25 genes have been implicated in familial (fALS) and sporadic ALS (sALS) forms 6 , suggesting a wide heterogeneity in the molecular bases of the disease. Several ALS-causing genes encode proteins involved in RNA metabolism processes, such as RNA transcription, splicing, mRNA transport and microRNAs (miRNAs) biogenesis 7. Dysfunction of these mechanisms is not exclusive and may lead to diverse cellular abnormalities. Epigenetic mechanisms, such as miRNAs, could regulate the expression of genes involved in common cellular pathways that are disrupted in ALS and therefore have an impact on ALS phenotype 8. MiRNAs are small, non-coding RNA molecules of approximately 22 nucleotides that regulate gene

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Section: Discussionmentioning

confidence: 99%

Downregulation of miR-335-5P in Amyotrophic Lateral Sclerosis Can Contribute to Neuronal Mitochondrial Dysfunction and Apoptosis

Luna

Turon-Sans

Cortés-Vicente

et al. 2020

Sci Rep

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“…Our results suggest that impaired biogenesis of memory-promoting miRNAs could be an additional non-genomic mechanism of cognitive impairment in neurodegenerative disorders. Future studies should consider a role for impaired biogenesis of additional miRNAs known to regulate memory formation, such as miR-132/212 [15], miR-335 [4], miR-12 [28], miR-124 [28], miR-181a [44], and miR-29b [21] in neurodegenerative disorders. Furthermore, cognitive alterations observed in ALS are pleiotropic with pronounced frontal-mediated behavioral dysfunctions in a vast majority of patients [41] and surprisingly low rates of depression despite physical disability [35].…”

Section: Discussionmentioning

confidence: 99%

“…Pri-miRNA processing assays were conducted as previously described [4,5]. Briefly, fragments of pri-mir-182 and pri-mir-183 containing the hairpin and 100 bp flanking sequence were amplified from genomic DNA.…”

Section: Luciferase-based Pri-mirna Processingmentioning

confidence: 99%

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

et al. 2018

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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.

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“…Brain-specific miR - 124a is also critical for the differentiation and maturation of dentate gyrus neurons and retinal cone cells [14]. In addition, miR - 335 - 5p plays a key role in spatial memory formation and hippocampal plasticity [15]. Therefore, miRNAs are key regulators of mammalian neurodevelopment and have been increasingly linked to neuronal differentiation and the translatability of mRNAs in neurons.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-24-3p regulates neuronal differentiation by controlling hippocalcin expression

Kang

Park

Han

2019

Cell. Mol. Life Sci.

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Hippocalcin (HPCA) is a neuron-specific calcium-binding protein predominantly expressed in the nervous system. In the present study, we demonstrate that HPCA regulates neuronal differentiation in SH-SY5Y cells. We observed that the expression level of HPCA was increased during neuronal differentiation. Depletion of HPCA inhibited both neurite outgrowth and synaptophysin (SYP) expression, whereas overexpression of HPCA enhanced neuronal differentiation. Interestingly, we also found that the expression of HPCA mRNA was modulated by miR-24-3p. Using a dual-luciferase assay, we showed that co-transfection of a plasmid containing the miR-24-3p binding site from the 3′-untranslated region (3′UTR) of the HPCA gene and an miR-24-3p mimic effectively reduced luminescence activity. This effect was abolished when miR-24-3p seed sequences in the 3′UTR of the HPCA gene were mutated. miR-24-3p expression was decreased during differentiation, suggesting that the decreased expression level of miR-24-3p might have upregulated mRNA expression of HPCA. As expected, upregulation of miR-24-3p by an miRNA mimic led to reduced HPCA expression, accompanied by diminished neuronal differentiation. In contrast, downregulation of miR-24-3p by an antisense inhibitor promoted neurite outgrowth as well as levels of SYP expression. Taken together, these results suggest that miR-24-3p is an important miRNA that regulates neuronal differentiation by controlling HPCA expression.Electronic supplementary materialThe online version of this article (10.1007/s00018-019-03290-3) contains supplementary material, which is available to authorized users.

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MicroRNA-335-5p modulates spatial memory and hippocampal synaptic plasticity

Cited by 29 publications

References 35 publications

Downregulation of miR-335-5P in Amyotrophic Lateral Sclerosis Can Contribute to Neuronal Mitochondrial Dysfunction and Apoptosis

Downregulation of miR-335-5P in Amyotrophic Lateral Sclerosis Can Contribute to Neuronal Mitochondrial Dysfunction and Apoptosis

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

MicroRNA-24-3p regulates neuronal differentiation by controlling hippocalcin expression

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