Login Register Cart 0
Mini-Review Article

Non-coding RNAs in Regulation of Protein Aggregation and Clearance Pathways: Current Perspectives Towards Alzheimer's Research and Therapy

Author(s): Sonali Sundram, Neerupma Dhiman*, Rishabha Malviya and Rajendra Awasthi*

Volume 24, Issue 1, 2024

Published on: 09 August, 2023

Page: [8 - 16] Pages: 9

DOI: 10.2174/1566523223666230731093030

Price: $65

conference banner
Abstract

Alzheimer's disease (AD) is the leading cause of dementia, affecting approximately 45.0 million people worldwide and ranking as the fifth leading cause of mortality. AD is identified by neurofibrillary tangles (NFTs), which include abnormally phosphorylated tau-protein and amyloid protein (amyloid plaques). Peptide dysregulation is caused by an imbalance between the production and clearance of the amyloid-beta (Aβ) and NFT. AD begins to develop when these peptides are not cleared from the body. As a result, understanding the processes that control both normal and pathological protein recycling in neuronal cells is critical. Insufficient Aβ and NFT clearance are important factors in the development of AD. Autophagy, lysosomal dysfunction, and ubiquitin-proteasome dysfunction have potential roles in the pathogenesis of many neurodegenerative disorders, particularly in AD. Modulation of these pathways may provide a novel treatment strategy for AD. Non-coding RNAs (ncRNAs) have recently emerged as important biological regulators, with particular relevance to the emergence and development of neurodegenerative disorders such as AD. ncRNAs can be used as potential therapeutic targets and diagnostic biomarkers due to their critical regulatory functions in several biological processes involved in disease development, such as the aggregation and accumulation of Aβ and NFT. It is evident that ncRNAs play a role in the pathophysiology of AD. In this communication, we explored the link between ncRNAs and AD and their regulatory mechanisms that may help in finding new therapeutic targets and AD medications.

Keywords: Alzheimer's disease, dementia, neurodegenerative disorder, tau protein, Non-coding RNAs, motor skills impairment.

« Previous Next »
Graphical Abstract

[1]
Hussain R, Zubair H, Pursell S, Shahab M. Neurodegenerative diseases: Regenerative mechanisms and novel therapeutic approaches. Brain Sci 2018; 8(9): 177.
[http://dx.doi.org/10.3390/brainsci8090177] [PMID: 30223579]
[2]
2023 Alzheimer’s disease facts and figures. Alzheimers Dement 2023; 19(4): 1598-695.
[http://dx.doi.org/10.1002/alz.13016] [PMID: 36918389]
[3]
Weglinski C, Jeans A. Amyloid-β in Alzheimer’s disease: Front and centre after all? Neuronal Signal 2023; 7(1): NS20220086.
[http://dx.doi.org/10.1042/NS20220086] [PMID: 36687366]
[4]
Rawat P, Sehar U, Bisht J, Selman A, Culberson J, Reddy PH. Phosphorylated tau in alzheimer’s disease and other tauopathies. Int J Mol Sci 2022; 23(21): 12841.
[http://dx.doi.org/10.3390/ijms232112841] [PMID: 36361631]
[5]
Ajmal MR. Protein misfolding and aggregation in proteinopathies: causes, mechanism and cellular response. Diseases 2023; 11(1): 30.
[http://dx.doi.org/10.3390/diseases11010030] [PMID: 36810544]
[6]
Tecalco-Cruz AC, Pedraza-Chaverri J, Briones-Herrera A, Cruz-Ramos E, López-Canovas L, Zepeda-Cervantes J. Protein degradation-associated mechanisms that are affected in Alzheimer’s disease. Mol Cell Biochem 2022; 477(3): 915-25.
[http://dx.doi.org/10.1007/s11010-021-04334-8] [PMID: 35083609]
[7]
Frankowska N, Lisowska K, Witkowski JM. Proteolysis dysfunction in the process of aging and age-related diseases. Frontiers in Aging 2022; 3: 927630.
[http://dx.doi.org/10.3389/fragi.2022.927630] [PMID: 35958270]
[8]
Vilchez D, Saez I, Dillin A. The role of protein clearance mechanisms in organismal ageing and age-related diseases. Nat Commun 2014; 5(1): 5659.
[http://dx.doi.org/10.1038/ncomms6659] [PMID: 25482515]
[9]
Boland B, Yu WH, Corti O, et al. Promoting the clearance of neurotoxic proteins in neurodegenerative disorders of ageing. Nat Rev Drug Discov 2018; 17(9): 660-88.
[http://dx.doi.org/10.1038/nrd.2018.109] [PMID: 30116051]
[10]
Hipp MS, Kasturi P, Hartl FU. The proteostasis network and its decline in ageing. Nat Rev Mol Cell Biol 2019; 20(7): 421-35.
[http://dx.doi.org/10.1038/s41580-019-0101-y] [PMID: 30733602]
[11]
Sengupta S. Noncoding RNAs in protein clearance pathways: implications in neurodegenerative diseases. J Genet 2017; 96(1): 203-10.
[http://dx.doi.org/10.1007/s12041-017-0747-1] [PMID: 28360406]
[12]
Wang M, Qin L, Tang B. MicroRNAs in Alzheimer’s disease. Front Genet 2019; 10: 153.
[http://dx.doi.org/10.3389/fgene.2019.00153] [PMID: 30881384]
[13]
Peplow PV, Martinez B. MicroRNAs as diagnostic and therapeutic tools for Alzheimer’s disease: Advances and limitations. Neural Regen Res 2019; 14(2): 242-55.
[http://dx.doi.org/10.4103/1673-5374.244784] [PMID: 30531004]
[14]
Idda ML, Munk R, Abdelmohsen K, Gorospe M. Noncoding RNAs in Alzheimer’s disease. Wiley Interdiscip Rev RNA 2018; 9(2): e1463.
[http://dx.doi.org/10.1002/wrna.1463] [PMID: 29327503]
[15]
Statello L, Guo CJ, Chen LL, Huarte M. Gene regulation by long non-coding RNAs and its biological functions. Nat Rev Mol Cell Biol 2021; 22(2): 96-118.
[http://dx.doi.org/10.1038/s41580-020-00315-9] [PMID: 33353982]
[16]
Hombach S, Kretz M. Non-coding RNAs: Classification, biology and functioning. Adv Exp Med Biol 2016; 937: 3-17.
[http://dx.doi.org/10.1007/978-3-319-42059-2_1] [PMID: 27573892]
[17]
Losko M, Kotlinowski J, Jura J. Long Noncoding RNAs in metabolic syndrome related disorders. Mediators Inflamm 2016; 2016: 1-12.
[http://dx.doi.org/10.1155/2016/5365209] [PMID: 27881904]
[18]
Morey C, Avner P. Employment opportunities for non-coding RNAs. FEBS Lett 2004; 567(1): 27-34.
[http://dx.doi.org/10.1016/j.febslet.2004.03.117] [PMID: 15165889]
[19]
Guennewig B, Cooper AA. The central role of noncoding RNA in the brain. Int Rev Neurobiol 2014; 116: 153-94.
[http://dx.doi.org/10.1016/B978-0-12-801105-8.00007-2] [PMID: 25172475]
[20]
Wu YY, Kuo HC. Functional roles and networks of non-coding RNAs in the pathogenesis of neurodegenerative diseases. J Biomed Sci 2020; 27(1): 49.
[http://dx.doi.org/10.1186/s12929-020-00636-z] [PMID: 32264890]
[21]
Taylor JP, Hardy J, Fischbeck KH. Toxic proteins in neurodegenerative disease. Science 2002; 296(5575): 1991-5.
[http://dx.doi.org/10.1126/science.1067122] [PMID: 12065827]
[22]
Lim J, Yue Z. Neuronal aggregates: Formation, clearance, and spreading. Dev Cell 2015; 32(4): 491-501.
[http://dx.doi.org/10.1016/j.devcel.2015.02.002] [PMID: 25710535]
[23]
Petrella C, Di Certo MG, Barbato C, et al. Neuropeptides in Alzheimer’s disease: An update. Curr Alzheimer Res 2019; 16(6): 544-58.
[http://dx.doi.org/10.2174/1567205016666190503152555] [PMID: 31456515]
[24]
O’Brien RJ, Wong PC. Amyloid precursor protein processing and Alzheimer’s disease. Annu Rev Neurosci 2011; 34(1): 185-204.
[http://dx.doi.org/10.1146/annurev-neuro-061010-113613] [PMID: 21456963]
[25]
Vu Nguyen K. β-Amyloid precursor protein (APP) and the human diseases. AIMS Neurosci 2019; 6(4): 273-81.
[http://dx.doi.org/10.3934/Neuroscience.2019.4.273] [PMID: 32341983]
[26]
Kolarova M, García-Sierra F, Bartos A, Ricny J, Ripova D. Structure and pathology of tau protein in Alzheimer disease. Int J Alzheimers Dis 2012; 2012: 1-13.
[http://dx.doi.org/10.1155/2012/731526] [PMID: 22690349]
[27]
Martin L, Latypova X, Terro F. Post-translational modifications of tau protein: Implications for Alzheimer’s disease. Neurochem Int 2011; 58(4): 458-71.
[http://dx.doi.org/10.1016/j.neuint.2010.12.023] [PMID: 21215781]
[28]
Buée L, Bussière T, Buée-Scherrer V, Delacourte A, Hof PR. Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res Brain Res Rev 2000; 33(1): 95-130.
[http://dx.doi.org/10.1016/S0165-0173(00)00019-9] [PMID: 10967355]
[29]
Kadavath H, Hofele RV, Biernat J, et al. Tau stabilizes microtubules by binding at the interface between tubulin heterodimers. Proc Natl Acad Sci 2015; 112(24): 7501-6.
[http://dx.doi.org/10.1073/pnas.1504081112] [PMID: 26034266]
[30]
Matsui T, Ingelsson M, Fukumoto H, et al. Expression of APP pathway mRNAs and proteins in Alzheimer’s disease. Brain Res 2007; 1161: 116-23.
[http://dx.doi.org/10.1016/j.brainres.2007.05.050] [PMID: 17586478]
[31]
Estrada L, Soto C. Disrupting β-amyloid aggregation for Alzheimer disease treatment. Curr Top Med Chem 2007; 7(1): 115-26.
[http://dx.doi.org/10.2174/156802607779318262] [PMID: 17266599]
[32]
Hommen F, Bilican S, Vilchez D. Protein clearance strategies for disease intervention. J Neural Transm 2022; 129(2): 141-72.
[http://dx.doi.org/10.1007/s00702-021-02431-y] [PMID: 34689261]
[33]
Jayaraj GG, Hipp MS, Hartl FU. Functional modules of the proteostasis network. Cold Spring Harb Perspect Biol 2020; 12(1): a033951.
[http://dx.doi.org/10.1101/cshperspect.a033951] [PMID: 30833457]
[34]
Fecto F, Esengul Y, Siddique T. Protein recycling pathways in neurodegenerative diseases. Alzheimers Res Ther 2014; 6(2): 13.
[http://dx.doi.org/10.1186/alzrt243] [PMID: 25031631]
[35]
Bukau B, Weissman J, Horwich A. Molecular chaperones and protein quality control. Cell 2006; 125(3): 443-51.
[http://dx.doi.org/10.1016/j.cell.2006.04.014] [PMID: 16678092]
[36]
Miller DJ, Fort PE. Heat shock proteins regulatory role in neurodevelopment. Front Neurosci 2018; 12: 821.
[http://dx.doi.org/10.3389/fnins.2018.00821] [PMID: 30483047]
[37]
Chen JJ, Lin F, Qin ZH. The roles of the proteasome pathway in signal transduction and neurodegenerative diseases. Neurosci Bull 2008; 24(3): 183-94.
[http://dx.doi.org/10.1007/s12264-008-0183-6] [PMID: 18500392]
[38]
Melino G. Discovery of the ubiquitin proteasome system and its involvement in apoptosis. Cell Death Differ 2005; 12(9): 1155-7.
[http://dx.doi.org/10.1038/sj.cdd.4401740] [PMID: 16094390]
[39]
Goldberg AL. Protein degradation and protection against misfolded or damaged proteins. Nature 2003; 426(6968): 895-9.
[http://dx.doi.org/10.1038/nature02263] [PMID: 14685250]
[40]
Lambert-Smith IA, Saunders DN, Yerbury JJ. The pivotal role of ubiquitin-activating enzyme E1 (UBA1) in neuronal health and neurodegeneration. Int J Biochem Cell Biol 2020; 123: 105746.
[http://dx.doi.org/10.1016/j.biocel.2020.105746] [PMID: 32315770]
[41]
Ross CA, Poirier MA. Protein aggregation and neurodegenerative disease. Nat Med 2004; 10(S7) (Suppl.): S10-7.
[http://dx.doi.org/10.1038/nm1066] [PMID: 15272267]
[42]
Zhang T, Pang P, Fang Z, et al. Expression of BC1 impairs spatial learning and memory in Alzheimer’s disease via APP translation. Mol Neurobiol 2018; 55(7): 6007-20.
[http://dx.doi.org/10.1007/s12035-017-0820-z] [PMID: 29134514]
[43]
Ciarlo E, Massone S, Penna I, et al. An intronic ncRNA-dependent regulation of SORL1 expression affecting Aβ formation is upregulated in post-mortem Alzheimer’s disease brain samples. Dis Model Mech 2012; 6(2): dmm.009761.
[http://dx.doi.org/10.1242/dmm.009761] [PMID: 22996644]
[44]
Taylor HA, Przemylska L, Clavane EM, Meakin PJ. BACE1: More than just a β-secretase. Obes Rev 2022; 23(7): e13430.
[http://dx.doi.org/10.1111/obr.13430] [PMID: 35119166]
[45]
Andersen OM, Reiche J, Schmidt V, et al. Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein. Proc Natl Acad Sci 2005; 102(38): 13461-6.
[http://dx.doi.org/10.1073/pnas.0503689102] [PMID: 16174740]
[46]
Deng Y, Xiao L, Li W, et al. Plasma long noncoding RNA 51A as a stable biomarker of Alzheimer’s disease. Int J Clin Exp Pathol 2017; 10(4): 4694-9.
[47]
Long JM, Ray B, Lahiri DK. MicroRNA-153 physiologically inhibits expression of amyloid-β precursor protein in cultured human fetal brain cells and is dysregulated in a subset of Alzheimer disease patients. J Biol Chem 2012; 287(37): 31298-310.
[http://dx.doi.org/10.1074/jbc.M112.366336] [PMID: 22733824]
[48]
Bartel DP. MicroRNAs: Target recognition and regulatory functions. Cell 2009; 136(2): 215-33.
[http://dx.doi.org/10.1016/j.cell.2009.01.002] [PMID: 19167326]
[49]
Kleinberger G, Yamanishi Y, Suárez-Calvet M, et al. TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis. Sci Transl Med 2014; 6(243): 243ra86.
[http://dx.doi.org/10.1126/scitranslmed.3009093] [PMID: 24990881]
[50]
Tiribuzi R, Crispoltoni L, Porcellati S, et al. miR128 up-regulation correlates with impaired amyloid β(1-42) degradation in monocytes from patients with sporadic Alzheimer’s disease. Neurobiol Aging 2014; 35(2): 345-56.
[http://dx.doi.org/10.1016/j.neurobiolaging.2013.08.003] [PMID: 24064186]
[51]
Patel N, Hoang D, Miller N, et al. MicroRNAs can regulate human APP levels. Mol Neurodegener 2008; 3(1): 10.
[http://dx.doi.org/10.1186/1750-1326-3-10] [PMID: 18684319]
[52]
Zhang H, Liang J, Chen N. The potential role of miRNA-regulated autophagy in Alzheimer’s disease. Int J Mol Sci 2022; 23(14): 7789.
[http://dx.doi.org/10.3390/ijms23147789] [PMID: 35887134]
[53]
Kim J, Fiesel FC, Belmonte KC, et al. miR-27a and miR-27b regulate autophagic clearance of damaged mitochondria by targeting PTEN-induced putative kinase 1 (PINK1). Mol Neurodegener 2016; 11(1): 55.
[http://dx.doi.org/10.1186/s13024-016-0121-4] [PMID: 27456084]
[54]
Yang L, Wang H, Shen Q, Feng L, Jin H. Long non-coding RNAs involved in autophagy regulation. Cell Death Dis 2017; 8(10): e3073.
[http://dx.doi.org/10.1038/cddis.2017.464] [PMID: 28981093]
[55]
Xu X, Cui L, Zhong W, Cai Y. Autophagy-associated lncRNAs: Promising targets for neurological disease diagnosis and therapy. Neural Plast 2020; 2020: 1-13.
[http://dx.doi.org/10.1155/2020/8881687] [PMID: 33029125]
[56]
Cortini F, Roma F, Villa C. Emerging roles of long non-coding RNAs in the pathogenesis of Alzheimer’s disease. Ageing Res Rev 2019; 50: 19-26.
[http://dx.doi.org/10.1016/j.arr.2019.01.001] [PMID: 30610928]
[57]
Ballantyne MD, McDonald RA, Baker AH. lncRNA/MicroRNA interactions in the vasculature. Clin Pharmacol Ther 2016; 99(5): 494-501.
[http://dx.doi.org/10.1002/cpt.355] [PMID: 26910520]
[58]
Massone S, Vassallo I, Fiorino G, et al. 17A, a novel non-coding RNA, regulates GABA B alternative splicing and signaling in response to inflammatory stimuli and in Alzheimer disease. Neurobiol Dis 2011; 41(2): 308-17.
[http://dx.doi.org/10.1016/j.nbd.2010.09.019] [PMID: 20888417]
[59]
Asadi MR, Hassani M, Kiani S, et al. The perspective of dysregulated LncRNAs in Alzheimer’s Disease: A systematic scoping review. Front Aging Neurosci 2021; 13: 709568.
[http://dx.doi.org/10.3389/fnagi.2021.709568] [PMID: 34621163]
[60]
Zhang M, He P, Bian Z. Long noncoding rnas in neurodegenerative diseases: Pathogenesis and potential implications as clinical biomarkers. Front Mol Neurosci 2021; 14: 685143.
[http://dx.doi.org/10.3389/fnmol.2021.685143] [PMID: 34421536]
[61]
Huang Z, Zhao J, Wang W, Zhou J, Zhang J. Depletion of LncRNA NEAT1 rescues mitochondrial dysfunction through NEDD4L-dependent PINK1 degradation in animal models of Alzheimer’s disease. Front Cell Neurosci 2020; 14: 28.
[http://dx.doi.org/10.3389/fncel.2020.00028] [PMID: 32140098]
[62]
Pathak GA, Silzer TK, Sun J, et al. Genome-wide methylation of mild cognitive impairment in mexican americans highlights genes involved in synaptic transport, alzheimer’s disease-precursor phenotypes, and metabolic morbidities. J Alzheimers Dis 2019; 72(3): 733-49.
[http://dx.doi.org/10.3233/JAD-190634] [PMID: 31640099]
[63]
Zhao MY, Wang GQ, Wang NN, Yu QY, Liu RL, Shi WQ. The long-non-coding RNA NEAT1 is a novel target for Alzheimer’s disease progression via miR-124/BACE1 axis. Neurol Res 2019; 41(6): 489-97.
[http://dx.doi.org/10.1080/01616412.2018.1548747] [PMID: 31014193]
[64]
Matsuda S, Kitagishi Y, Kobayashi M. Function and characteristics of PINK1 in mitochondria. Oxid Med Cell Longev 2013; 2013: 1-6.
[http://dx.doi.org/10.1155/2013/601587] [PMID: 23533695]
[65]
Zhou Y, Ge Y, Liu Q, et al. LncRNA BACE1-AS promotes autophagy-mediated neuronal damage through the miR-214-3p/ATG5 signaling axis in Alzheimer’s disease. Neuroscience 2021; 455: 52-64.
[http://dx.doi.org/10.1016/j.neuroscience.2020.10.028] [PMID: 33197504]
[66]
Faghihi MA, Zhang M, Huang J, et al. Evidence for natural antisense transcript-mediated inhibition of microRNA function. Genome Biol 2010; 11(5): R56.
[http://dx.doi.org/10.1186/gb-2010-11-5-r56] [PMID: 20507594]
[67]
Memczak S, Jens M, Elefsinioti A, et al. Circular RNAs are a large class of animal RNAs with regulatory potency. Nature 2013; 495(7441): 333-8.
[http://dx.doi.org/10.1038/nature11928] [PMID: 23446348]
[68]
Shao Y, Chen Y. Roles of circular RNAs in neurologic disease. Front Mol Neurosci 2016; 9: 25.
[http://dx.doi.org/10.3389/fnmol.2016.00025] [PMID: 27147959]
[69]
Sierksma A, Lu A, Salta E, et al. Deregulation of neuronal miRNAs induced by amyloid-β or TAU pathology. Mol Neurodegener 2018; 13(1): 54.
[http://dx.doi.org/10.1186/s13024-018-0285-1] [PMID: 30314521]
[70]
Banzhaf-Strathmann J, Benito E, May S, et al. Micro RNA ‐125b induces tau hyperphosphorylation and cognitive deficits in Alzheimer’s disease. EMBO J 2014; 33(15): 1667-80.
[http://dx.doi.org/10.15252/embj.201387576] [PMID: 25001178]
[71]
Smith PY, Hernandez-Rapp J, Jolivette F, et al. miR-132/212 deficiency impairs tau metabolism and promotes pathological aggregation in vivo. Hum Mol Genet 2015; 24(23): 6721-35.
[http://dx.doi.org/10.1093/hmg/ddv377] [PMID: 26362250]

Rights & Permissions Print Cite
Article Metrics
34
2
Wayfinder Image
© 2024 Bentham Science Publishers | Privacy Policy