Parkinson’s disease (PD) is a neurodegenerative disease characterized by bradykinesia, rigidity, and tremor. Age is the main risk factor. Long noncoding RNAs (lncRNAs) are novel RNA molecules of more than 200 nucleotides in length. They may be involved in the regulation of many pathological processes of PD. PD has a variety of pathophysiological mechanisms, including alpha-synuclein aggregate, mitochondrial dysfunction, oxidative stress, calcium homeostasis, axonal transport, and neuroinflammation. Among these, the impacts of lncRNAs on the pathogenesis and progression of PD need to be highlighted. lncRNAs may serve as putative biomarkers and therapeutic targets for the early diagnosis of PD. This study aimed to investigate the role of lncRNAs in various pathological processes of PD and the specific lncRNAs that might be used as putative diagnostic biomarkers and therapeutic targets of PD.
Parkinson’s disease (PD) is a common neurodegenerative disease, second only to Alzheimer’s disease (AD) [
Recent studies focus on the pathogenesis of PD at both the microscopic biological and macroscopic anatomical levels to find an effective therapy [
Despite the noteworthy advances in understanding the etiology and the high-throughput drug screening methods for small molecules, remarkable developments in disease modeling, and improvements in analytical technologies, no therapies are available to prevent the disease from getting worse [
Long noncoding RNA (lncRNA) is a new potential biomarker with biological functions [
lncRNAs function by interacting with three kinds of biomolecules: DNA, RNA, and protein [
lncRNAs are highly enriched and expressed in the central nervous system (CNS) [
The abnormal expression of lncRNAs is closely associated with several human neurological diseases, including PD, AD, Huntington’s disease, and schizophrenia [
Multiple functions of long noncoding RNAs (lncRNAs) in pathological changes of Parkinson’s disease.
Existing studies have confirmed that lncRNAs are highly expressed in various parts of both the CNS and the brain [
LncRNAs: their mechanism of action in Parkinson’ disease.
lncRNA | Tissue/model | Regulation | Pathway targeted by the lncRNAs | References |
---|---|---|---|---|
AS UCHL1 | (1) MN9D cells treated with MPP+ | Down | AS Uchl1 RNA, as a component of Nurr1-dependent gene network and target of cellular stress, extended the understanding on the role of antisense transcription in the brain | [ |
(2) DA neurons from PD model treated with MPP+ | ||||
HAGLROS | MPTP-induced PD mice and SH-SY5Y cells treated with MPP+ | Up | Suppression of HAGLRO decreased apoptosis and autophagy in both | [ |
HAGLRO negatively regulated miR-100 expression | ||||
Suppression of HAGLROS alleviated MPP(+)-intoxicated SH-SY5Y cell injury by activating PI3K/AKT/mTOR pathway | ||||
HOTAIR | SH-SY5Y cells treated with MPP+ | Up | With HOTAIR overexpression in SH-SY5Y cells, the expression of LRRK2 increased compared with that in the control | [ |
HOTAIR knockdown provided protection against MPP(+)-induced DA neuronal apoptosis by repressing caspase 3 activity | ||||
MALAT1 | MPTP-induced PD mice and SH-SY5Y cells treated with MPP+ | Up | MALAT1 knockdown attenuated MPTP-induced apoptosis of DA neurons in MPTP-induced PD mouse model | [ |
MALAT1 interacted with miR-124 to negatively regulate its expression | ||||
MPTP-induced PD mice and SH-SY5Y cells treated with MPP+ | Up | MALAT1 was associated with a-synuclein, leading to the increased stability of a-synuclein and its expression | [ | |
MPTP-induced PD mice and MN9D cells treated with MPP+ | Up | MALAT1/miR-205-5p axis regulates MPP(+)-induced apoptosis in MN9D cells by targeting LRRK2 | [ | |
MPTP-induced PD mice and SH-SY5Y cells treated with MPP+ | Up | MALAT1 knockdown attenuated MPP(+)-induced apoptosis of DA neurons in SH-SY5Y cells | [ | |
MALAT1 regulates DAPK1 expression by targeting miR-124-3p | ||||
MAPT-AS1 | Brain tissue samples (10 patients with PD and 10 controls) | Down | MAPT-AS1 and DNMT1 have been identified as potential epigenetic regulators of MAPT expression in PD | [ |
Mirt2 | SY5Y cells treated with TNF- | Down | Mirt2 exhibited anti-inflammatory properties through miR-101 suppression | [ |
Mirt2 blocked TNF | ||||
NEAT1 | MPTP-induced PD mice and SH-SY5Y cells treated with MPP+ | Up | NEAT1 knockdown promoted cell viability and suppressed cell apoptosis | [ |
Downregulation of NEAT1 also decreased the ratio of Bax/Bcl-2, the activity of caspase-3, as well as the expression of | ||||
MPTP-induced PD mice and SH-SY5Y cells treated with MPP+ | Up | NEAT1 positively regulated the protein level of PINK1 through inhibition of PINK1 protein degradation | [ | |
NEAT1 knockdown could effectively suppress MPTP-induced autophagy that alleviated dopaminergic neuronal injury | ||||
lincRNA-p21 | SH-SY5Y cells treated with MPP+ | Up | lincRNA-p21 regulated MPP(+)-induced neuronal injury by sponging miR-625 and upregulating TRPM2 in SH-SY5Y cells | [ |
MPTP-induced PD mice and SH-SY5Y cells treated with MPP+ | Up | lincRNA-p21 sponged miR-1277-5p and indirectly increased the expression of | [ | |
MPTP-induced PD mice and SH-SY5Y cells treated with a CM transfer system were used to determine the impact of LPS-treated BV2 cells | Up | p53/lincRNA-p21, together with miR-181/PKC- | [ | |
SNHG1 | MPTP-induced PD mice and SH-SY5Y cells treated with MPP+ | Up | SNHG1 could directly bind to miR-15-5p and repress miR-15-5p expression | [ |
Upregulation of miR-15b-5p alleviated | ||||
SNHG1 knockdown inhibited | ||||
MN9D cells treated with MPP+ | Up | SNHG1 could competitively bind to the miR-221/222 cluster and indirectly regulate the expression of p27/mTOR | [ | |
SH-SY5Y cells treated with MPP+ | Up | SNHG1 overexpression lowered viability and enhanced apoptosis in MPP(+)-treated SH-SY5Y cells. | [ | |
H19 | MPTP-induced PD mice and human neuroblastoma cells treated with MPP+ | Down | H19 attenuates apoptosis in MPTP-induced Parkinson's disease | [ |
H19/miR-585-3p axis regulates MPP(+)-induced apoptosis in human neuroblastoma cells cells by targeting PIK3R3 | ||||
UCA1 | 6-OHDA-induced PD rat | Up | Downregulation of lncRNA UCA1 ameliorates the damage of dopaminergic neurons, reduces oxidative stress and inflammation in PD rats | [ |
Downregulation of lncRNA UCA1 inhibits the PI3K/Akt signaling pathway. |
Altered lncRNAs in Parkinson’ Disease.
Tissue | Ethnicity/population | LncRNA | Regulation | References |
---|---|---|---|---|
Substantia nigra and cerebellum (9 patients with PD and 8 controls) | Not mentioned (the tissue were obtained from The Netherlands brain Bank) | AK127687, AX747125, GBAP1, SNCA-AS1, UCHL1-AS1, PINK1-AS1, and MAPT-AS1 | Up | [ |
Anterior cingulate gyrus (20 patients with PD and 10 controls) | Not mentioned (the tissue were provided by the Neurobiobank Munich (NBM)) | H19 upstream conserved 1 and 2 | Up | [ |
LincRNA-p21, MALAT1, SNHG1, and TncRNA | Down | |||
Exosomes isolated from CSF (47 patients with PD and 27 controls) | Not mentioned (the tissue were provided by the sir Run Run shaw hospital, affiliated with school of medicine, Zhejiang University) | RP11-462G22.1 and PCA3 | Up | [ |
Extracellular RNAs present in CSF (27 patients with PD and 30 controls) | Not mentioned (the tissue were provided by the hospital Universitario Donostia, San Sebastian, Spain (MDUD)) | AC079630 and UC001lva.4 (close to the LRRK2 gene locus) | Up | [ |
Substantia nigra (11 patients with PD and 14 controls) | Not mentioned (the volunteers who provided the tissue were from USA, UK, Israel, and Germany) | AL049437, U79277, AF052141, AK021454, BC018626, AF147723, AK001884, AY365119, BC151247, BC151234, AK311445, AK310272, AK094351, AF007131, AF119861, CR619166, AK023852, AK074162, AF052176, BC007937, AK025388, AK022431, CR618512, AK021912, AL109681, AF090884, AL359578, AF070543, AK021798, AK024568, U94902, AK024381, AF090910, BC002644, BC064478, AF007141, M28219, AK001998, BC002821, AL049328, AK024684, and AK000420 | Up | [ |
AK024198, AK025097, AK024214, AF052148, AF070579, AK023918, AK022167, AK024938, AL109707, BC000988, AK025271, AL109705, AJ001873, BC029383, AK025360, | Down | |||
Blood leukocytes sample (3 patients with PD) | Not mentioned | RP11-101C11.1, U1 | Up | [ |
RP11-409K20.6, RP4-705O1.1, AC004744.3, RP11-533O20.2, and RP11-542K23.9 | Down | |||
Brain tissue samples (10 patients with PD and 10 controls) | Caucasian descent (the tissue were provided by the Sydney Brain Bank and the NSW Tissue Resource Centre) | MAPT-AS1 | Down | [ |
Plasma samples (32 patients with PD and 13 controls) | Not mentioned (the volunteers who provided the tissue were from Beijing Tiantan Hospital) | MSTRG.242001.1, MSTRG.169261.1 | Up | [ |
MSTRG.336210.1, lnc-MKRN2-42 : 1 | Down | |||
Substantia nigra from mice (3 Nrf2+/+ mice and 3 Nrf2-/- mice) | AK020441, AK020330, NR_003555, NR_073442, AK040987, ENSMUST00000142871, ENSMUST00000153819, ENSMUST00000132304, uc011ysu.1, and so forth (a total of 74) | Up | [ | |
ENSMUST00000139383, NR_024325, AK047372, ENSMUST00000156693, ENSMUST00000181307, AK076880, AK036620, TCONS_00017218, TCONS_00022981, TCONS_00004085, and so forth (a total of 160) | Down | |||
Whole mesencephalic tissues from mice (6 | uc.44-, BC037523, and so forth (a total of 164) | Up | [ | |
uc.12+, AK076860, and so forth (a total of 177) | Down | |||
The striatum from rat (9 PD model and 9 control rats) | XLOC_026924, XLOC_029397, XLOC_004631, XLOC_005439, XLOC_018657, XLOC_016191, XLOC_022926, AABR07029901.1, XLOC_025867, XLOC_016202, and so forth (a total of 451) | Up | [ | |
XLOC_028318, XLOC_037769, XLOC_029657, XLOC_010572, XLOC_017775, XLOC_018598, Rn50_5_1638.1, XLOC_006399, AABR07027137.1, XLOC_001547, and so forth (a total of 61) | Down | |||
SY-SH5Y cells treated with a-synuclein oligomers | A total of 53 lncRNAs | Up | [ | |
A total of 69 lncRNAs | Down | |||
Whole mesencephalic tissues from mice (6 | uc.44-, BC037523, and so forth (a total of 164) | Up | [ | |
uc.12+, AK076860, and so forth (a total of 177) | Down |
lncRNAs detected in the aforementioned studies were different because of different sampling locations and detection techniques, besides differences between individuals. They play an important role in the pathological process of PD and may serve as a potential diagnostic marker and therapeutic target for PD. Furthermore, they may also be used to quantify the efficacy of medication and surgery in patients. However, obtaining a large number of multicenter databases to quantify lncRNA changes in PD is difficult due to the high cost of sequencing technology. However, with the progress of science and technology, lncRNAs have a great potential as a diagnostic marker and therapeutic target for PD.
Currently, six widely recognized sites, including SNCA (alpha-synuclein), Parkin (PARK2), PINK1 (PARK6), DJ-1 (PARK7), LRRK2 (PARK8), and ATP13A2 (PARK9), can cause hereditary single-gene PD [
Alpha-synuclein is a protein closely related to neurodegenerative diseases. It is an important part of the Lewy body, and its abnormal aggregation is associated with PD, Lewy body dementia, and multisystem atrophy [
Three therapeutic views exist on the role of alpha-synuclein in PD: reducing the expression of SNCA by directly silencing or inhibiting its promoter expression, activating autophagy or proteasome to increase protein clearance, and reducing posttranslation-based modification [
A dynamic balance exists in the expression of alpha-synuclein in normal individuals. The balance is maintained by the actions of the ubiquitin-proteasome system and the lysosomal autophagy system (LAS). The LAS is more important than the ubiquitinproteasome system in mediating alpha-synuclein degradation in neurons [
In conclusion, lncRNAs can be targeted to restore and strengthen the cell homeostasis of patients, maintain the balance of the autophagy system, and further eliminate alpha-synuclein as a potential treatment for PD.
The apoptosis of dopaminergic neurons is the characteristic pathological manifestation of PD. Various lncRNAs play different roles in this process. lncRNA HOTAIR was highly expressed in the MPTP-induced PD mouse model and MPP(+)-induced PD cell model. HOTAIR specifically improved the stability of LRRK2 mRNA (LRRK2 mutations are widely recognized as the most common cause of dominant PD, and LRRK2 is one of the risk factors for PD [
Slowing down the progression of the disease by targeting the regulation of these apoptosis-related lncRNAs is a promising therapeutic option.
Neuroinflammation is regarded as one of the most common contributors to PD [
Increasing scientific data show that certain lncRNAs alter differentially over time in the brains of patients with PD [
Although the research of lncRNA as a biomarker in PD is still in its infancy, it is exciting that, in certain research areas, clinical trials have started on lncRNA as a biomarker [
As the expression level of lncRNA in PD is related to the initiation and progression of PD and its symptoms, it can be used as a potential therapeutic target for PD. It is possible to target lncRNA to regulate its expression in a variety of ways. For example, the use of lncRNA-specific siRNA, such as the downregulation of siRNA-mediated MALAT1 expression can inhibit MPP(+)-induced apoptosis of DA neurons [
The research on lncRNAs is in the initial stages. An increasing number of studies have been conducted on the role of lncRNAs in PD in the last three years. Some studies have shown that lncRNAs are involved in the initiation and progression of PD. A large number of lncRNAs have been found to provide a new basis for the development of early diagnosis and treatment of PD, and the expression of lncRNAs can also be used to predict the symptoms of PD patients. Previous studies have found that some lncRNAs play a protective role in PD (such as UCHL1, MAPT-AS1, and Mirt2), and some of them aggravate the disease progression (such as HOTAIR, MALAT1, NEAT1, lincrna-p21, and SNHG1). Now, many challenges in the study of lncRNAs cannot be ignored. For example, lncRNAs do not have a uniform nomenclature. Compared with coding genes, lncRNAs account for a small proportion, and it is difficult to determine the role of lncRNAs according to nucleotide sequences [
The authors declare that they have no conflicts of interest regarding the publication of this article.
Qiankun Lv wrote the manuscript, Ziyu Wang contributed to figure generation, Zhen Zhong contributed to table generation, and Wei Huang was involved in the project design, supervision, and manuscript revision. All authors read and approved the final manuscript.
The authors acknowledge the support and help from Professor Huang. They thank MedSci for linguistic assistance during the preparation of this manuscript. This study was funded by the Key Research and Development Project of Jiangxi Province (grant no. 20171BBG70065).