Abstract
Alternative pre-mRNA splicing plays a very important role in expanding protein diversity as it generates numerous transcripts from a single protein-coding gene. Therefore, alterations lead this process to neurological human disorders, including Alzheimer’s and Parkinson’s diseases. Moreover, accumulating evidence indicates that the splicing machinery highly contributes to the cells’ ability to adapt to different altered cellular microenvironments, such as hypoxia. Hypoxia is known to have an effect on the expression of proteins involved in a multiple of biological processes, such as erythropoiesis, angiogenesis, and neurogenesis, and is one of the important risk factors in neuropathogenesis. In this review, we discuss the current knowledge of alternatively spliced genes, which, as it is reported, are associated with Alzheimer’s and Parkinson’s diseases. Additionally, we highlight the possible influence of cellular hypoxic microenvironment for the formation of mRNA isoforms contributing to the development of these neurodegenerative diseases.
Highlights
Alternative splicing of precursor messenger RNA is one of the most important co-transcriptional and post-transcriptional regulatory mechanisms responsible for the regulation of gene expression and generation of proteomic and functional diversity [1,2,3]
It demonstrated that the significant involvement of hypoxia in the processes of neuron degeneration, where hypoxia upregulates β-site APP cleaving enzyme BACE1 gene transcription leading to increased BACE1 secretase activity and production of neurotoxic amyloid β peptide [66,72]
The described findings complement the picture of hypoxia influence on the development of neurodegenerative disorders
Summary
Alternative splicing of precursor messenger RNA (pre-mRNA) is one of the most important co-transcriptional and post-transcriptional regulatory mechanisms responsible for the regulation of gene expression and generation of proteomic and functional diversity [1,2,3]. Several other factors, including neurotoxic effects, genetic predisposition, or traumatic brain injury, contribute to the progression of neuropathology [9,10]. NNeotincaglelyn,ethtiics dfaiscetaosresc,asnubcehfaams ibliraalionr stpraouramdiac,atnydpeear2lydoirablaeteteosn, seent v[1i3r]o.nMmosetnptaatliefnatcstors, and (o~t9h5e%rs),aaplpsoeacrotontbreibsupoteratdoicparondgruessusaiollny owfitshploarteadoincseAtDag[e1(3o]l.dDeretshpainte65tryeemaresn).dNoounsgper-ogress in ntheteickfnacotworlse,dsugcehoafstbhreaimn toraleucmuala, tryppaet2hdoigabeenteessi,senovfiAroDnm, tehnetaclofamctpolrest,eanudnodtehresrtsa, anldsoing of the croenastroibnustfeortodepvroeglorepsmsioenntooff sApDorardemic aAinDs e[1lu3]s.ivDee[s7p]i.te tremendous progress in the knowPleadrgkeinosf othne’smdoilseecauslaer (pPaDth)o,gtehneessiescoofnAdDm, tohsetccoommplmetoenunndeeursrtoadnedginegnoefrathtievreead-isease, is saosnssocfoiartdeedvewloipthmseenlteocftiAvDe dreemgeainnesrealtuiosinveo[f7]n.igrostriatal dopaminergic neurons, othePr anrekuinrsootnra’sndsimseiatster(PsDys),tethmesse(ic.oen.,dgmluotsatmcoamtemrgoinc,ncehuorolidneegregnice,ratrtiyvpetdaimseianser, gisica,s-noradrenseorcgiiact,edadwreitnhersgeliecc,tisveerodteogneinneerragtiiocn, aonf dnipgeropsttirdiaetragl idc)opaalsmoinaeprpgiecanr etuorobnes,afaflethctoeudgh[14]. It is ostthaeterdntehuarot t~ra5n0s%miottfetrhseynstiegmrasl(ni.ee.u, rgolnustammautsetrgdiec,gechnoelrianteergtioc,ptrroydptuacmeinaesrygmic,pntoorma- complex dcorennseirsgtiinc,gaodfretnreemrgiocr,,sreirgoitdointyin, eprogsict,uarnadl ipnesptatibdielirtgyi,c)analdsobarpadpeyakrintoesbiea.afIfnecatedddi[t1i4o]n. Ceiumrreern’tsraensedarPcahrkinson’s sduigsegaestesst[h1a7t,1p8re].-mRNA splicing is heavily altered in Alzheimer’s and Parkinson’s diseases [17,18]
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