Small Molecule Drugs Targeting Non-Coding RNAs as Treatments for Alzheimer’s Disease and Related Dementias
Abstract
:1. Introduction
1.1. ncRNAs as Novel Therapeutic Targets for Treating ADRD
1.2. Small Molecule Drugs for Modulation of ncRNAs
2. Discovery and Validation of Small Molecules Targeting ncRNAs
2.1. Selection of Compound Libraries and Cellular or Animal Models
2.2. Cell-Based Reporter Assays for Discovering Regulators of ncRNAs
2.3. Biochemical Assays for Discovering Direct Binders of ncRNAs
2.4. Assays for Discovering Small Molecules Modulating RNA–Protein Interaction
2.5. RNA-seq for Discovering Small Molecules That Modulate ncRNA Levels and Networks
2.6. Validation and Optimization of Candidate Small Molecules from Primary HTSs
3. Examples of ADRD-Relevant ncRNAs and Screening Strategies
3.1. Selecting ncRNA Targets and Screening Strategies
3.2. Upregulating miR-132, a miRNA Commonly Downregulated in ADRD
3.3. Inhibiting BACE1-AS, a lncRNA Upregulated in ADRD
3.4. Modulating the Splicing Efficiency of circRNAs Dysregulated in ADRD
4. Conclusions and Future Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
AD | Alzheimer’s disease |
ADRD | Alzheimer’s disease and related dementias |
ALIS | Automated ligand identification system |
APP | Amyloid–β precursor protein |
AS | Antisense transcript |
ASO | Antisense oligonucleotide |
BACE1-AS | β-secretase 1 antisense transcript |
BBB | Blood–brain barrier |
BDNF | Brain-derived neurotropic factor |
Cat-ELCCA | Catalytic enzyme-linked click chemistry assay |
CDR1-AS | Cerebellar degeneration-related protein 1 antisense RNA |
Chem-CLIP-Map-Seq | Chemical Cross-Linking and Isolation by Pull-down to Map Small Molecule-RNA Binding Sites |
ChIP-seq | Chromatin immunoprecipitation-RNA-seq |
circRNA | Circular RNA |
CREB | cAMP response element-binding protein |
DGCR8 | DiGeorge critical region 8 |
DRUG-seq | Digital RNA with perturbation of Genes |
ENCODE | Encyclopedia of DNA Elements |
Exp5 | Exportin 5 |
FANTOM | Functional Annotation of the Mammalian Genome |
FDA | Food and Drug Administration |
FID | Fluorescent indicator displacement |
FP | Fluorescence polarization |
FRET | Fluorescence resonance energy transfer |
FTD | Frontotemporal dementia |
HD | Huntington’s disease |
HOTAIR | HOX antisense intergenic RNA |
HTS | High-throughput screen |
HTT | Huntingtin |
ITC | Isothermal titration calorimetry |
LBD | Lewy body dementia |
LC-MS | Liquid chromatography-mass spectrometry |
lncRNA | Long non-coding RNA |
MALAT1 | Metastasis-associated lung adenocarcinoma transcript 1 |
MED | Multiple etiology dementias |
miRNA | MicroRNA |
MoA | Mechanism of action |
mRNA | Messenger RNA |
ncRNA | Non-coding RNA |
NMR | Nuclear magnetic resonance |
PAIN | Pan-assay interference |
PDB | Protein data bank |
PK/PD | Pharmacokinetics and pharmacodynamics |
PRC2 | Polycomb repressive complex 2 |
PSEN1 | Presenilin 1 |
PSEN2 | Presenilin 2 |
RBP | RNA binding protein |
REST | RE1-silencing transcription factor |
RISC | RNA-induced silencing complex |
rRNA | Ribosomal RNA |
shRNA | Short hairpin RNA |
siRNA | Small interfering RNA |
SMN2 | Survival of motor neuron 2 |
sncRNA | Small ncRNA |
snoRNA | Small nucleolar RNA |
snRNA | Small nuclear RNA |
SPR | Surface plasmon resonance |
TORNADO-seq | Targeted organoid sequencing |
TRBP | Transactivating response RNA-binding protein |
tRNA | Transfer RNA |
VCID | Vascular contributions to cognitive impairment and dementia |
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Small non-coding RNAs: ncRNAs of <200 nucleotides. | |
MicroRNAs | ncRNAs of 18–25 nucleotides that facilitate the degradation or inhibit the translation of mRNA targets through imperfect complementary base pairings. |
Piwi-interacting RNAs | ncRNAs of 26–31 nucleotides that facilitate the silencing of transposons in germline cells, may also have other functions in somatic cells. |
tRNA-derived small RNAs | tRNA-derived fragments of 14–30 nucleotides and tRNA halves of 30–50 nucleotides produced from precursor or mature tRNAs. Emerging evidence suggests that they function as signaling molecules in stress responses and as regulators of gene expression. |
Long non-coding RNAs (lncRNAs): ncRNAs of >200 nucleotides, with largely elusive functions. They can be further classified by the genomic loci from which they are transcribed. | |
Intergenic lncRNAs | lncRNAs transcribed from regions not overlapping with protein-coding genes. |
Intronic lncRNAs | lncRNAs produced from introns of protein-coding genes. |
Sense-overlapping lncRNAs | lncRNAs transcribed from regions overlapping with introns and exons of protein-coding genes. |
Bidirectional lncRNAs | lncRNAs transcribed from the same promoters of protein-coding genes, but in the opposite direction. |
Antisense lncRNAs | lncRNAs transcribed from the antisense RNA strands of protein-coding genes. |
Enhancer RNAs | lncRNAs transcribed from genomic enhancer regions. |
Circular RNAs | Closed single-stranded lncRNAs produced by back-splicing, in which the 5′ and 3′ termini of linear RNAs are covalently joined by spliceosome-mediated splicing. Most known circRNAs are transcribed from protein-coding genes. |
Pseudogene transcripts | RNAs transcribed from DNA sequences that resemble protein-coding genes but lack the ability to produce functional proteins. These transcripts maybe processed into siRNAs or function as endogenous miRNA sponges. |
RNA Species | Evidence of Dysregulation in Human ADRD | Signaling Pathways and Genes Affected | Therapeutic Application and Potential | |
---|---|---|---|---|
In Cell Lines | In Animal Models | |||
Small ncRNAs | ||||
miR-132 | Downregulated in AD hippocampus, prefrontal cortex, temporal cortex [82,83,84,85,86,87,88,89]; significantly associated with Braak score in some studies Downregulated in FTD frontal cortex [90,91] | Aβ homeostasis: ITPKB, ERK1/2, BACE1 [87] Tau homeostasis: MAPT, CAPN2, RBFOX1, GSK-3β, EP300, PP2B, ITPKB [82,87,92,93] Neuronal apoptosis: PTEN, FOXO3a [82] Neurogenesis and synaptic plasticity: p250GAP, MeCP2, BDNF [94,95,96] | miR-132 viral overexpression or mimics rescued peroxide, glutamate, and Aβ toxicity in primary rodent and human neurons [82,92] | Viral overexpression and mimics rescued hippocampal cell death, tau homeostasis [92,93], hippocampal adult neurogenesis, and behavioral deficits in various AD mouse models [93,96] |
miR-107 | Downregulated in AD neocortex and temporal cortex [97,98] | Aβ homeostasis: BACE1 [97,98] | miR-107 mimics rescued glutamate and Aβ toxicity in primary rodent and human neurons [92] | |
miR-101 | Downregulated in AD temporal cortex [99,100] | Aβ homeostasis: BACE1, APP, Aβ42 [99,100,101,102] | miR-101 overexpression reduced Aβ load in rat hippocampal neurons [102] | Viral overexpression of miR-101 sponge in mouse hippocampus induced memory deficits [101] |
miR-195 | Downregulated in AD parietal cortex tissue [103] | Aβ homeostasis: BACE1 [104] Lysosomal defects: SYNJ1 [103] | Overexpression of miR-195 rescued lysosomal defects in iPSC-derived neurons from ADRD patients [103] and decreased Aβ plaque in N2a cells [104] | Viral overexpression in mouse models decreased Aβ plaque, tau hyperphosphorylation and rescued cognitive deficits in ApoE4+/+ mice [103] |
miR-34a | Upregulated in AD temporal cortex [88,105] | Aβ homeostasis: ADAM10 [106] Tau homeostasis: PTPA [106] Synaptic plasticity: VAMP, SYT1, HCN1, NR2A, GluR1, SIRT1 [105,106] | miR-34a mimics exacerbated, whereas miR-34a inhibitor protected against glutamate and Aβ toxicity in primary rodent and human neurons [92] | Overexpression of miR-34a induces rapid cognitive impairment in mouse model [106] |
miR-26b | Upregulated in AD temporal cortex [107] | Tau homeostasis: CDK5 [107] Aberrant cell cycle entry: RB1 [107] | miR-26b inhibition protects mouse and human primary neurons against peroxide and Aβ toxicity [92,107] | |
miR-203 | Upregulated in FTD frontal cortex [108] | Genes in the neurodegeneration-associated synaptic (NAS) module: BCL2L2, DGKB, MAPK10, VSNL1 [108] | Overexpressing mi-203 in mouse primary cortical neurons increased apoptosis [108] | Upregulation of miR-203 and corresponding downregulation of predicted targets in the cortex of TPR50 tau mice [108] |
piRNAs | Various piRNA dysregulated in AD prefrontal cortex [109,110] | |||
Linear lncRNAs | ||||
BACE1-AS (β Secretase Antisense Transcript) | Upregulated in AD cerebellum, hippocampus, cortex, and serum [111,112,113] | Aβ homeostasis: BACE1, Aβ42 [111,112,113,114] | Knockdown BACE1-AS in SH-SY5Y cells reduced Aβ toxicity [113] | Hippocampal injection of BACE1-AS inhibitors reduced neuronal death in APP/PS1 mice [113] Activation of NRF2 by sulforaphane inhibited BACE1 and BACE1-AS transcription and rescued cognitive deficits in 5xFAD mice [114] |
NEAT1 (Nuclear Enriched Abundant Transcript 1) | Upregulated in AD temporal cortex and hippocampus [89,115,116] | Autophagy: NEDD4L, PINK1 [117] Synaptic plasticity: promotes H3K9 dimethylation of c-Fos promoter to suppress c-Fos expression [118] | Overexpression of NEAT1 exacerbated peroxide injury in N2A cells [119] | Hippocampal knockdown of NEAT1 with siRNA improved memory in aged mice and vice versa [118] Viral knockdown of NEAT1 rescued memory deficit in APP/PS1 mice [117] |
17A | Upregulated in AD cortex [120] | Neurogenesis: nestin [121] Autophagy: LC3B [121] | Overexpression of 17A in SH-SY5Y cells increased Aβ secretion [120] Downregulation of 17A in SH-SY5Y cells decreased apoptosis and Aβ42 secretion [121] | |
BC200 | Upregulated in AD cortex and hippocampus [122] | Aβ homeostasis: APP [123] | Hippocampal overexpression of rodent homolog BC1 increased APP and Aβ expression and impaired memory, whereas inhibiting BC1 was neuroprotective [123] | |
Enhancer RNAs | Various enhancer RNAs dysregulated in AD prefrontal cortex [124] | |||
circRNAs | ||||
CDR1-AS (Cerebellar Degeneration-Related Protein 1 Antisense Transcript) | Downregulated in AD temporal cortex and hippocampus [125,126] Upregulated in AD parietal cortex [127] | Aβ homeostasis: BACE1, APP [128] Neuronal activity: miR-7 sponge, c-Fos, EGR1, ARC [129,130] | CDR1-AS overexpression promoted lysosomal degradation of BACE1 and APP proteins in HEK293 and SH-SY5Y cells [128] CDR1-AS KO neurons showed dysfunctional synaptic neurotransmission [130] | Cdr1-as KO mice showed impaired sensorimotor gating, but normal memory acquisition [130] |
circHOMER1 (circ-Homer Protein Homolog 1) | Downregulated in AD parietal [127] and frontal cortex [131], significantly associated with Braak score | |||
circKCNN2 (circ-Potassium Calcium-Activated Channel Subfamily N Member 2) | Downregulated in AD parietal [127] and frontal cortex [131], significantly associated with Braak score | |||
circDOCK1 (circ-Dedicator Of Cytokinesis 1) | Upregulated in AD parietal [127] and frontal cortex [131], significantly associated with Braak score |
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Nguyen, L.D.; Chau, R.K.; Krichevsky, A.M. Small Molecule Drugs Targeting Non-Coding RNAs as Treatments for Alzheimer’s Disease and Related Dementias. Genes 2021, 12, 2005. https://doi.org/10.3390/genes12122005
Nguyen LD, Chau RK, Krichevsky AM. Small Molecule Drugs Targeting Non-Coding RNAs as Treatments for Alzheimer’s Disease and Related Dementias. Genes. 2021; 12(12):2005. https://doi.org/10.3390/genes12122005
Chicago/Turabian StyleNguyen, Lien D., Rachel K. Chau, and Anna M. Krichevsky. 2021. "Small Molecule Drugs Targeting Non-Coding RNAs as Treatments for Alzheimer’s Disease and Related Dementias" Genes 12, no. 12: 2005. https://doi.org/10.3390/genes12122005