Non-coding RNAs and their bioengineering applications for neurological diseases

Figures & data

Figure 1. Cellular fates of miRNA and LncRNA maturation. (a) microRNAs, transcribed as primary transcripts from intergenic (pri-miRNA) or, intronic regions (mirtrons, non-canonical). DROSHA-DiGeorge syndrome critical region 8 (DGCR8) complex processes the pri-mRNA structures to produce precursor (pre-mRNA) sequence which is exported from the nucleus to the cytosol for further processing by DICER1 and helicase activity to produce a mature 18–22nts long sequence that undergoes ribonucleoprotein (RNP) assembly with the family of Argonaute proteins (AGO1-4), called as RNA-induced silencing complex (RISC) complex. (b) Long non-coding RNAs are products of Pol II transcription from intergenic regions. They are presumed to undergo processing events including capping, splicing and polyadenylation, in some cases. From left – Natural anti-sense transcripts are transcribed from the opposite(complementary) strands of mRNAs (usually coding in nature). Anti-sense lncRNA and MALAT-1 associated RNA (mascRNA) are produced because of RNAse P processing. U-A-U triple helix at the 3ʹends of mascRNA provides structural stability. sno polyadenylated RNAs (SPA) are 3ʹpolyadenylated and produced from read-through transcripts that are assembled with sno ribonuclear proteins (snoRNPs). In contrast, sno-lncRNAs lack a 5ʹm⁷G cap and 3ʹ poly (A) tail and are produced from excited introns post splicing events. Finally, the circular intronic RNAs (ciRNAs) are also a product of intron excision post splicing events often produced as an outcome of 3ʹexonuclease activity

Table 1. List of non-coding RNAs (miRNAs, lncRNAs) detected in the brain regions and cerebrospinal fluid of patients suffering from neurological diseases

Alzheimer’s disease
ncRNA species	Patient brain region	References
mir-29	Hippocampus	[130–133]
miR-15, miR-125, miR-146, miR-222, miR-29	Cerebrospinal fluid
miR-15, miR-153, miR-455-3p, miR-219	Brain tissue
miR-46, miR-9, miR-101, miR-106	Cortex, Hippocampus
miR-125b, miR-107	Cortex tissue
miR-140-5p	Cerebellum, Hippocampus
miR-501-3p, miR-93	Serum
NDM29, 17A	Cerebral Cortex
GDNFOS, MALAT1	Cerebrospinal fluid
Parkinson’s disease
miR-30 family	Substantia Nigra	[76,134–137]
miR-29 family	Mesencephalon, Prefrontal cortex
Let-7 family	Mesencephalon, Prefrontal cortex, Substantia Nigra
miR-485	Substantia Nigra, Caudate Putamen
miR-26	Striatum, Substantia Nigra
miR-200	Midbrain tissue
miR-151	Prefrontal cortex
miR-1, miR-28, miR-374	Substantia Nigra
miR-200a-3p, miR-542-3p, miR-144-5p, miR-151a-3p, let-7 f-5p, miR-27a-3p, miR-125a-5p, miR-423-5p	Cerebrospinal fluid
AK127687, UCHL1-AS1, and MAPT-AS1	Cerebellum
HOTAIRM1, lnc-MOK-6:1, and RF01976.1–201	Circulating PBMCs
lincRNA-p21, Malat1, SNHG1	Brain tissue
Schizophrenia
GOMAFU	Cortical gray matter, Superior temporal gyrus	[102,138,139]
PINT, GAS5, IFNG-AS1, FAS-AS1	Blood, PBMC in circulation
Huntington’s disease
HAR1F, HAR1R	Striatum	[133,140,141]
HTTAS_v1	Frontal cortex
Neat1	Brain tissue

Table 2. List of non-coding RNAs (miRNAs, lncRNAs) with their respective genetic targets reported in neurological disorders

Alzheimer’s disease
ncRNA species	Direct and indirect molecular targets	References
miR-9 family (miR-9-5p)	GSK-3β, CAMKK2, SIRT1	[142–144]
miR-146 family (miR-146a)	ROCK1, CFH, TRAF-6, IL-1, IRAK-1	[145,146]
miR-125b	FOXQ1, PTGS2, CDK5, DUSP6, PPP1CA, Bcl-W	[147,148]
miR-124	BACE-1, PTPN, NR3C1	[149–151]
miR-107	BACE-1, FGF-7	[152,153]
BACE1-AS	BACE-1	[154,155]
51A	SORL1	[156]
BDNF-AS	BDNF, GDNF, EPHB2	[156]
NAT-Rad18	RAD18	[157]
LRP1-AS	LRP1, HMGB2	[158]
Parkinson’s disease
miR-30 family	SNCA, PARK2, LRRK2, ATG5, USP6, NEDD4, USP3	[78,80,159]
miR-29 family	DNMT3A, TET2	[160,161]
Let-7 family	E2F1	[162]
miR-181	p38 MAPK/JNK, PARK2	[163,164]
miR-26	PTEN, PINK1, TGF-β/JNK pathway, TAK1, TAB3	[76]
lincRNA-p21	sponge for the miR-181 family	[165]
NaPINK1	PINK1	[166]
UCHL1-AS1	UCH-L1	[167]
MALAT1	SNCA	[135]
HOTAIR	LRRK2	[168]
SNHG1	NLRP3	[169]
Schizophrenia
AC006129.1	SOCS3, CASP1	[170]
Gomafu/MIAT	QK1, SRSF, SF1, DISC1, ERBB4	[30,171]
miR-132	DNMT3A, GATA2, DPYSL3, PTBP2, MMP-9, STAT-4	[172,173]
miR‐30a miR‐195	BDNF	[174]
BDNF-AS	BDNF	[175]
miR-212	MMP-9, MeCP2, STAT4, ZO-1	[173]
miR-137	NRG2/3, SYN2/3, ATXN1, ERBB4, GSK3B, FZD3, PTGS2	[176]
Huntington’s disease
HTTAS_v1	HTT	[177]
miR-124	PGC1, BDNF, SOX9	[178]
miR-29 c	P53	[179,190]
MEG3	HTT	[180]
TUG1	P53	[181]

Figure 2. Bioengineering of ncRNAs for biomedical applications. Both miRNAs and lncRNAs can be used for several therapeutic and diagnostic applications based on the bioengineering approaches used that include encapsulation of ncRNAs in functionalized nanoparticles, lipid/polymer based nanocarriers, terminal modifications including biotin or fluorophore tagging or chemical modifications by adding functional groups (i.e., 2ʹO-Methyl, P = S bonds) or by bridging the 2ʹoxygen with 4ʹcarbon as represented in the figure

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