Current Status of microRNA-Based Therapeutic Approaches in Neurodegenerative Disorders
Abstract
:1. Introduction
2. Overview of miRNA Therapeutics
3. Delivery Techniques for miRNA Therapeutics
4. Alzheimer’s Disease (AD)
5. Parkinson’s Disease (PD)
6. Huntington’s Disease (HD)
7. Amyotrophic Lateral Sclerosis (ALS)
8. Friedreich’s Ataxia (FRDA)
9. Spinal Muscular Atrophy (SMA)
10. Frontotemporal Dementia
11. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Disorder | Targeted MiRNA | Antagonist or Mimics | Target Gene | Delivery Method | Biological Model or Tissue | Functional Implication | Reference |
---|---|---|---|---|---|---|---|
Alzheimer’s Disease (AD) | miR-16 | Mimics | APP, BACE1 | Liposomes | HEK293 cells | Reduced expression of BACE1 and APP | [42] |
miR-16,15,195 | HEK293 cells overexpressing APP Swedish mutation | Suppression of Aβ production | |||||
miR-16 | Neuro2a cells | Reduction of BACE1 and APP protein expression, decrease in Tau phosphorylation | |||||
HT22 cells | Reduction of BACE1 and APP protein expression | ||||||
APP, BACE1, Tau | Oligonucleotide | Mice | APP downregulated in cortex, brainstem, and striatum. BACE1 reduced in the hippocampus, brainstem, and striatum. Tau downregulation in the hippocampus, brainstem, and striatum. ERK1 downregulated in the hippocampus and cortex. Nicastrin, Gfap, and Aif1 downregulation | ||||
miR-132 | Mimics | Tau | Liposomes | Neuro2a cells cotransfected with a reporter construct containing mouse 3’UTR | Downregulation of tau expression | [43] | |
Neuro2a cells | |||||||
Cell transfection | 3xTg-AD mice | Improve long term memory and reduction of phosphorylated tau | |||||
miR-132 | Mimics | ITPKB | Oligonucleotide | Mice | Amelioration of amyloidosis and Tau hyperphosphorylation | [44] | |
miR-124 | Mimics | BACE1 | Oligonucleotide | Hippocampal neurons, PC12 cells | Reduction of BACE1 expression and Aβ production | [45] | |
miR-193a-3p | Mimics | PTEN | Liposomes | PC12 cells, SH-SY5Y cells | Attenuation of β-amyloid induced neurotoxicity | [46] | |
miR-107 | Mimics | PDCD10 | Liposomes | PC12 cells, SH-SY5Y cells | Increase of cell viability, Reduction of Caspase-3 activity, LDH release, and ROS levels, increase SOD levels. Reduction of induced cytotoxicity | [47] | |
Lentivirus | 6-OHDA induced mouse model | Suppression of 6-OHDA induced motor disorder | |||||
miR-326 | Mimics | VAV1 | Lentivirus | Mice | Improvement in cognitive function, inhibition of JNK signaling pathway, decrease in Aβ deposition, inhibit protein expression of VAV1 | [48] | |
miR-34c | Inhibitor | SIRT1 | Hippocampal injection | C57Bl/6J mice | Enhance memory, reinstate learning behavior and SIRT1 levels | [49] | |
miR-34c | Inhibitor | SYT1 | Intranasal administration | SAMP8 mice | Increase levels of SYT1, amelioration of cognitive function, enhance memory function, recovery of dendritic spine density | [50] | |
miR-188-5p | Mimics | NRP2 | Oligonucleotide | Primary hippocampal neurons from 5XFAD mice | Reverse synaptic damage induced by Aβ 1-42 and reduction in dendritic spine density, enhance cognitive function impairments | [51] | |
miR-149 | Mimics | APP, BACE1, Tau | Cell transfection | SH-SY5Y cells | Resilience to Aβ oligomer | [52] | |
mir-485 | BACE1, Tau | ||||||
miR-485 | APP, Syn1, Ppp3ca, Mapt, Snap25, Snca, DNM1 | ICV | C57B6 mice | Upregulation of APP, Syn1, Ppp3ca, Mapt, Snap25, Snca and protection against Aβ oligomers in males, downregulation of DNM1, Mapt and Snca in females | |||
miR-4723 | Snap25 | Downregulation of Snap25 in males | |||||
miR-149 | Creb1 | Increase of Creb1 in males | |||||
miR-200b,miR-200c | Mimics | S6K1 | Liposomes | Primary neuronal cells and SH-SY5Y cells | Suppression of cytotoxic damage caused by Aβ | [53] | |
miR-200b/c | Lipid nanoparticle | C57BL/6J and Tg2576 mice | Defensive effect against Aβ-induced toxicity | ||||
miR-31 | Mimics | BACE1 | Cell transfection | HT-22 cells | Decrease in BACE1 mRNA levels | [54] | |
APP, BACE1 | Lentivirus | 3xTg-AD mice | Amelioration of deficits in memory, reduced anxiety and could prevent the progression of cognitive decline | ||||
miR-16 | Mimics | APP | Liposomes | Neuroblastoma2a, NIH3T3 murine cells | Reduction of APP protein level | [55] | |
Infusion | SAMP and SAMR1 mice | ||||||
miR-592 | Inhibitor | KIAA0319 | Liposomes | Astrocytes | Promotion of astrocytes viability, decrease oxidative stress injury in ASTs, reduction in C-keap1 expression, activation of Keap1/Nrf2/ARE signaling pathway | [57] | |
miR-101 | Mimics | APP | Liposomes | HeLa cells | Reduction of APP levels | [58] | |
Liposomes | Hela, U373, PC12 cells | ||||||
miR-206 | Inhibitor | BDNF | Cell transfection | Neuro2a cells | Increase of BDNF protein levels | [56] | |
Primary hippocampal neurons | Increase of dendritic spine density, enhanced hippocampal neurogenesis | ||||||
Intranasal administration | Mice | Increase DFNF protein levels, enhanced synaptogenesis, and neurogenesis, improvement of memory function | |||||
Parkinson’s Disease (PD) | miR-205 | Mimics | LRRK2 | Liposomes | Cell lines, primary neuron cultures, and mouse midbrain dopaminergic neurons | Reducted expression of LRRK2 and prevention of neurite outgrowth defects | [62] |
mir30-hSNCA | Mimics | SNCA | AAV2/8 (unilateral SN injection) | Rats | Protection against the deficit in the forelimb and partial protection against TH-IR cell loss in the SN | [63] | |
miR-30e | Mimics | NLRP3 | miR-30e agomir injected using a catheter | MPTP-treated PD mice | Reduction of neuroinflammation and lowered expression of α-synuclein | [64] | |
miR-124 | Mimics | BIM | Exogenous delivery | MPTP-treated PD mice | Reduction of autophagy, apoptosis and lysosomal exhausting | [65] | |
miR-124 | Mimics | BIM | Cell transfection | MPP+-intoxicated SH-SY5Y cells | Reduction of autophagy, apoptosis and lysosomal exhausting | [65] | |
miR-124 | Mimics | Sox9 Jagged1 | Cell transfection with NPs | Neural stem cells and neuroblasts | Neuronal maturation and proliferation | [66,67] | |
miR-124 | Mimics | Sox9 Jagged1 | Injection of NPs in the lateral ventricle | (6-OHDA) lesioned mice | Neuronal migration to the olfactory bulb and damaged striatum | [66,67] | |
miR-181a | Mimics | Regulation of the p38 MAPK and JNK signaling pathways | Liposomes | Human MPP+-induced SK-N-SH neuroblastoma cells | Diminution of the autophagy process and apoptosis | [68] | |
miR-185 | Mimics | Regulation of the AMPK/mTOR signaling pathway | Liposomes | MPTP-treated SH-SY5Y cells | Diminution of the autophagy process and apoptosis | [69] | |
miR-183 | Mimics | OSMR | Liposomes | SN neurons from MPTP-treated PD mice | Apoptosis of SN neurons | [70] | |
miR-155 | - | MHCII | - | Mice with an entire deletion of the miR-155 | Regulation of the inflammation and neurodegeneration | [71] | |
miR-155 | Mimics | MHCII | Oligonucleotide treatment | Microglial cells | Inflammatory response associated with α-synuclein | [71] | |
miR-7 | Mimics | NLPR3 | Stereotactical injection into the striatum | MPTP-treated PD mice | Regulation of the NLPR3 inflammasome activation and reduction in the degeneration of dopaminergic neurons | [72] | |
miR-494-3p | Inhibitor | SIRT3 | Liposomes | MPP+-induced SH-SY5Y cells | Decrease of neurotoxicity and motor deterioration | [73] | |
miR-9-5p | Inhibitor | SIRT1 | Liposomes | MPP+-induced SH-SY5Y cells | Decrease of neurotoxicity, apoptosis, oxidative stress and inflammation | [75] | |
miR-96 | Inhibitor | CACNG5 | Injection of inhibitor | MPTP-treated PD mice | Inhibition of both apoptosis and iNOS by blocking the MAPK signaling pathway | [76] | |
miR-96 | Inhibitor | CACNG5 | Liposomes | SH-SY5Y cells | Increment of nigral cells | [76] | |
miR-216a | Mimics | Bax | Liposomes | MPP+-treated SK-SY5Y neuroblastoma cells | Decrease of neurotoxicity and apoptosis | [77] | |
Huntington’s Disease (HD) | mi306.12v16G | Artificial miRNA | HTT | AAV2/1 (bilateral injection in the striata) | Transgenic HD mice | Absence of preferential silencing | [84] |
mi268.5 | Artificial miRNA | HTT | AAV2/1 (bilateral injection in the striata) | Transgenic HD mice | Targeting of the mutant allele | [84] | |
miR-27a | Mimics | MDR-1 | Cell transfection | Derived neuronal stem cells | Reduction in the accumulation of mHTT | [85] | |
miR-196a | Mimics | HTT | Cell transfection | Human embryonic renal cells and neuroblastoma cells of mice | Decrease in the expression of mHTT | [86] | |
miR-196a | Mimics | HTT | Lentiviral transgenesis | Transgenic HD mice | Decrease in the expression of mHTT | [86] | |
miR-196a | Mimics | HTT | Lentiviral infection | HD-iPSCs | Decrease in the expression of mHTT | [86] | |
miR-196a | Mimics | RANBP10 | Liposomes | Primary cortical neurons | Differentiation and development of neuronal cells | [87] | |
miR-196a | Mimics | RANBP10 | The hsa-miR-196a-2 precursor was in the transgenic mice | Transgenic HD mice | Differentiation and development of neuronal cells | [87] | |
miR-132 | Mimics | MeCP2 | AAV9 (intracranial injection) | Transgenic HD mice | Symptom improvement and life extension | [88] | |
miR-124 | Mimics | RE1 silencing transcription factor | Exosomal delivery | Transgenic HD mice | Reduced expression of the RE1 silencing transcription factor | [89] | |
miR-124 | Mimics | SOX9 | Striatal injection | Transgenic HD mice | Increase of neurogenesis in the striatum and cortex and neuronal survival | [90] | |
miR-22 | Mimics | MAPK14 Trp53inp1 Rcor1 HDAC4 Rgs2 | Lentiviral infection | Cultures of primary cortical and striatal neurons | Apoptosis inhibition, decrease in the cumulation of HTT and targeting of different genes | [91] | |
miHTT | Artificial miRNA | HTT | AAV9 (striatal and cortical injection) | Transgenic HD sheep | Decrease in the cumulation of mHTT in the neostriatum | [92] | |
miHTT | Artificial miRNA | HTT | AAV5 (intracerebral administration) | Lentiviral HD rats | Reduction in the accumulation of mHTT | [93] | |
miHTT | Artificial miRNA | HTT | AAV5 (intracranial administration) | Transgenic HD minipig | Decrease in the cumulation of mHTT | [94] | |
miHTT | Artificial miRNA | HTT | AAV5 (intracranial injection) | Transgenic HD mice | Decrease in the cumulation of HTT, weight gain, longer life expectancy, and functional improvement | [95] | |
miHTT | Artificial miRNA | HTT | AAV5 (intrastriatal administration) | Hu128/21 mouse model of HD | Suppression of HTT | [96] | |
Amyotrophic Lateral Sclerosis (ALS) | miR-155 | Inhibitor (antagomir) | Src homology-2 domain-containing SHIP1 and suppressor of cytokine signaling-1 | ICV | SOD1G93A mice | Prolonged survival rate, slower disease progress | [105] |
miR-29a | Inhibitor (antagomir) | NAV3, BACE1 | ICV | SOD1G93A mice | Increased lifespan | [106] | |
amiRSOD1 | Artificial miRNA | SOD1 | AAV9 | SOD1G93A mice | Extended survival, delayed hindlimb paralysis, reduction of mutant human SOD1 | [108] | |
miC | Artificial miRNA | C9orf72 | AAV5 | HEK293T cells and iPSC-derived neurons | Silencing of C9orf72 | [104] | |
miR-SOD1 | Artificial miRNA | SOD1 | rAAVrh10 | Marmoset | Silencing of SOD1 | [109] | |
miR-SOD1 | Artificial miRNA | SOD1 | AAVrh10 (Intralingual and Intrapleural injection) | SOD1G93A mice | Delayed disease onset, prolonged survival, improved breathing | [110] | |
miR-SOD1 | Artificial miRNA | SOD1 | rAAVrh10 | SOD1G93A mice | Delayed disease onset, extended survival | [111] | |
Friedreich’s Ataxia (FRDA) | miR-886-3p | Inhibitor | FXN | Cell transfection | Fibroblast | Increase frataxin levels | [117] |
miR-124 | Mimics | FXN | Cell transfection | HEK-293 | Down-regulation of FRDA-3-UTR haplotype | [4] | |
Spinal Muscular Atrophy (SMA) | miR-146a | Inhibitor | Chodl | Endo-Porter peptide | iPSC-derived motor neurons | Restoration of neurite length | [125] |
miR-431 | Inhibitor | Chodl | Cell transfection | Motor neurons | Restoration of neurite length | [126] | |
miR-206 | Mimics | HDAC4 | Liposomes | Myoblast cell line C2C12 | FGFBP1 transcriptional up-regulation | [127] | |
miR-206 | Mimics | HDAC4 | ICV | Pups and mice | Down-regulation of NCX2, reduction in the severity and progress of SMA pathology | [128] | |
Frontotemporal Dementia (FTD) | miR-29b | Mimics | GRN | Liposomes | NIH3T3 and Hek293 cells | Regulation of the expression of hPGRN | [138] |
miR-124 | Mimics | Gria2 and Gria4 | AAV-GFP injection | tTA: CHMP2BIntron5 mice | Reduction of the expression of Gria2, Gria4 and improvement of social behavior | [139] | |
miR-132/212 | Mimics | TMEM106B | Liposomes | HEK293 and SHSY5Y cells | Reduction of TMEM106B mRNA levels | [140] | |
miR-107 | Mimics | GRN | Liposomes | H4 and HeLa cells | Reduction of GRN expression | [141] | |
miR-659 | Mimics | GRN | Liposomes | M17 and N2A neuroblastoma cells | Reduction of GRN expression | [142] |
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Paul, S.; Bravo Vázquez, L.A.; Pérez Uribe, S.; Roxana Reyes-Pérez, P.; Sharma, A. Current Status of microRNA-Based Therapeutic Approaches in Neurodegenerative Disorders. Cells 2020, 9, 1698. https://doi.org/10.3390/cells9071698
Paul S, Bravo Vázquez LA, Pérez Uribe S, Roxana Reyes-Pérez P, Sharma A. Current Status of microRNA-Based Therapeutic Approaches in Neurodegenerative Disorders. Cells. 2020; 9(7):1698. https://doi.org/10.3390/cells9071698
Chicago/Turabian StylePaul, Sujay, Luis Alberto Bravo Vázquez, Samantha Pérez Uribe, Paula Roxana Reyes-Pérez, and Ashutosh Sharma. 2020. "Current Status of microRNA-Based Therapeutic Approaches in Neurodegenerative Disorders" Cells 9, no. 7: 1698. https://doi.org/10.3390/cells9071698
APA StylePaul, S., Bravo Vázquez, L. A., Pérez Uribe, S., Roxana Reyes-Pérez, P., & Sharma, A. (2020). Current Status of microRNA-Based Therapeutic Approaches in Neurodegenerative Disorders. Cells, 9(7), 1698. https://doi.org/10.3390/cells9071698