Growing evidence has demonstrated that long non-coding RNAs (lncRNAs) play a critical role in Alzheimer’s disease (AD), which is characterized by sustained mitochondrial dysfunction, inevitable memory loss, and cognitive decline. However, the potential function of lncRNAs MIR600 Host Gene (MIR600HG) in AD remains unanswered.
Objective:
Our study aimed to investigate the role of MIR600HG and its related molecular mechanism in AD.
Methods:
The expression of MIR600HG was examined by qRT-PCR. The MIR600HG interacting proteins were identified by RNA pull-down assay and mass spectrometry and verified by RNA immunoprecipitation. Immunofluorescence staining was applied to examine the colocalization of PINK1 and NEDD4L. The PINK1 level and the activation of autophagy were detected by immunoblotting. Morris water maze test was performed to evaluate cognitive decline in AD mice model.
Results:
MIR600HG expression was elevated during aging in two different types of AD transgenic mouse models. Next, we found that increased MIR600HG directly interact with NEDD4L, which promoted PINK1 ubiquitination and degradation, and as well as autophagy activation. Additionally, MIR600HG promoted Aβ production and suppressed Cytochrome C Oxidase activity. Administration of AAV-shMIR600HG restored the Cytochrome C Oxidase activity and inhibited Aβ production. Furthermore, PINK1 overexpression or MIR600HG knockdown significantly ameliorated the cognitive impairment in APP/PS1 mice. PINK1 depletion recovered the spatial memory defect in the AAV-shMIR600HG injected APP/PS1 mice.
Conclusion:
MIR600HG was increased in AD and promoted AD pathogenesis. Targeting MIR600HG significantly improved cognitive function in AD mice, which could pave the way for exciting new avenues in AD therapeutic strategy research.
WoodH (2020) Mitochondrial dysfunction manifests in the early stages of Alzheimer disease. Nat Rev Neurol16, 242.
10.
StatelloL, GuoCJ, ChenLL, HuarteM (2021) Gene regulation by long non-coding RNAs and its biological functions. Nat Rev Mol Cell Biol22, 96–118.
11.
KoppF, MendellJT (2018) Functional classification and experimental dissection of long noncoding RNAs. Cell172, 393–407.
12.
MatsuiM, CoreyDR (2017) Non-coding RNAs as drug targets. Nat Rev Drug Discov16, 167–179.
13.
RansohoffJD, WeiY, KhavariPA (2018) The functions and unique features of long intergenic non-coding RNA. Nat Rev Mol Cell Biol19, 143–157.
14.
LaurettiE, DabrowskiK, PraticoD (2021) The neurobiology of non-coding RNAs and Alzheimer’s disease pathogenesis: Pathways, mechanisms and translational opportunities. Ageing Res Rev71, 101425.
15.
YangS, LimKH, KimSH, JooJY (2021) Molecular landscape of long noncoding RNAs in brain disorders. Mol Psychiatry26, 1060–1074.
16.
CortiniF, RomaF, VillaC (2019) Emerging roles of long non-coding RNAs in the pathogenesis of Alzheimer’s disease. Ageing Res Rev50, 19–26.
17.
HongH, MoY, LiD, XuZ, LiaoY, YinP, LiuX, XiaY, FangJ, WangQ, FangS (2020) Aberrant expression profiles of lncRNAs and their associated nearby coding genes in the hippocampus of the SAMP8 mouse model with AD. Mol Ther Nucleic Acids20, 140–154.
18.
ZhouY, GeY, LiuQ, LiYX, ChaoX, GuanJJ, DiwuYC, ZhangQ (2021) lncRNA BACE1-AS promotes autophagy-mediated neuronal damage through the miR-214-3p/ATG5 signalling axis in Alzheimer’s disease. Neuroscience455, 52–64.
19.
YamanakaY, FaghihiMA, MagistriM, Alvarez-GarciaO, LotzM, WahlestedtC (2015) Antisense RNA controls LRP1 Sense transcript expression through interaction with a chromatin-associated protein, HMGB2. Cell Rep11, 967–976.
20.
YaoY, LiN (2020) MIR600HG suppresses metastasis and enhances oxaliplatin chemosensitivity by targeting ALDH1A3 in colorectal cancer.BSR202. Biosci Rep40, 00390.
21.
JinWS, ShenLL, BuXL, ZhangWW, ChenSH, HuangZL, XiongJX, GaoCY, DongZ, HeYN, HuZA, ZhouHD, SongW, ZhouXF, WangYZ, WangYJ (2017) Peritoneal dialysis reduces amyloid-beta plasma levels in humans and attenuates Alzheimer-associated phenotypes in an APP/PS1 mouse model. Acta Neuropathol134, 207–220.
22.
YaoY, KangSS, XiaY, WangZH, LiuX, MullerT, SunYE, YeK (2021) A delta-secretase-truncated APP fragment activates CEBPB, mediating Alzheimer’s disease pathologies. Brain144, 1833–1852.
23.
SiZ, WangX (2020) The neuroprotective and neurodegeneration effects of heme oxygenase-1 in Alzheimer’s disease. J Alzheimers Dis78, 1259–1272.
24.
SierksmaA, Escott-PriceV, De StrooperB (2020) Translating genetic risk of Alzheimer’s disease into mechanistic insight and drug targets. Science370, 61–66.
25.
ArancioO (2020) What does the APP family do in the brain?Neuron108, 583–585.
WuYY, KuoHC (2020) Functional roles and networks of non-coding RNAs in the pathogenesis of neurodegenerative diseases. J Biomed Sci27, 49.
28.
ChenLL (2016) Linking long noncoding RNA localization and function. Trends Biochem Sci41, 761–772.
29.
YaoRW, WangY, ChenLL (2019) Cellular functions of long noncoding RNAs. Nat Cell Biol21, 542–551.
30.
ZhaoY, ZhangY, ZhangL, DongY, JiH, ShenL (2019) The potential markers of circulating microRNAs and long non-coding RNAs in Alzheimer’s disease. Aging Dis10, 1293–1301.
31.
YiJ, ChenB, YaoX, LeiY, OuF, HuangF (2019) Upregulation of the lncRNA MEG3 improves cognitive impairment, alleviates neuronal damage, and inhibits activation of astrocytes in hippocampus tissues in Alzheimer’s disease through inactivating the PI3K/Akt signaling pathway. J Cell Biochem120, 18053–18065.
32.
SongJ, XuQ, ZhangH, YinX, ZhuC, ZhaoK, ZhuJ (2018) Five key lncRNAs considered as prognostic targets for predicting pancreatic ductal adenocarcinoma. J Cell Biochem119, 4559–4569.
KongD, WanQ, LiJ, ZuoS, LiuG, LiuQ, WangC, BaiP, DuanSZ, ZhouB, GounariF, LyuA, LazarusM, BreyerRM, YuY (2020) DP1 activation reverses age-related hypertension via NEDD4L-mediated T-Bet degradation in T cells. Circulation141, 655–666.
35.
LeeDE, YooJE, KimJ, KimS, KimS, LeeH, CheongH (2020) NEDD4L downregulates autophagy and cell growth by modulating ULK1 and a glutamine transporter. Cell Death Dis11, 38.
36.
NovellasdemuntL, KucharskaA, JamiesonC, Prange-BarczynskaM, BauliesA, AntasP, van der VaartJ, GehartH, MauriceMM, LiVS (2020) NEDD4 and NEDD4L regulate Wnt signalling and intestinal stem cell priming by degrading LGR5 receptor. EMBO J39, e102771.
37.
ZhangT, PerizG, LuYN, WangJ (2020) USP7 regulates ALS-associated proteotoxicity and quality control through the NEDD4L-SMAD pathway. Proc Natl Acad Sci U S A117, 28114–28125.
38.
ZhangY, HeX, MengX, WuX, TongH, ZhangX, QuS (2017) Regulation of glutamate transporter trafficking by Nedd4-2 in a Parkinson’s disease model. Cell Death Dis8, e2574.
39.
DemarestTG, VarmaVR, EstradaD, BabbarM, BasuS, MahajanUV, MoaddelR, CroteauDL, ThambisettyM, MattsonMP, BohrVA (2020) Biological sex and DNA repair deficiency drive Alzheimer’s disease via systemic metabolic remodeling and brain mitochondrial dysfunction. Acta Neuropathol140, 25–47.
40.
PickettEK, RoseJ, McCroryC, McKenzieCA, KingD, SmithC, GillingwaterTH, HenstridgeCM, Spires-JonesTL (2018) Region-specific depletion of synaptic mitochondria in the brains of patients with Alzheimer’s disease. Acta Neuropathol136, 747–757.
41.
Vaillant-BeuchotL, MaryA, Pardossi-PiquardR, BourgeoisA, LauritzenI, EysertF, KinoshitaPF, CazarethJ, BadotC, FragakiK, BussiereR, MartinC, MaryR, BauerC, PagnottaS, Paquis-FlucklingerV, Buee-ScherrerV, BueeL, Lacas-GervaisS, CheclerF, ChamiM (2021) Accumulation of amyloid precursor protein C-terminal fragments triggers mitochondrial structure, function, and mitophagy defects in Alzheimer’s disease models and human brains. Acta Neuropathol141, 39–65.
42.
FangEF, HouY, PalikarasK, AdriaanseBA, KerrJS, YangB, LautrupS, Hasan-OliveMM, CaponioD, DanX, RocktaschelP, CroteauDL, AkbariM, GreigNH, FladbyT, NilsenH, CaderMZ, MattsonMP, TavernarakisN, BohrVA (2019) Mitophagy inhibits amyloid-beta and tau pathology and reverses cognitive deficits in models of Alzheimer’s disease. Nat Neurosci22, 401–412.
