Parkinson's disease-related gene variants influence pre-mRNA splicing processes

Neurobiology of Aging
Katarzyna Gaweda-WalerychE Buratti

Abstract

We have analyzed the impact of Parkinson's disease (PD)-related genetic variants on splicing using dedicated minigene assays. Out of 14 putative splicing variants in 5 genes (PINK1, [PTEN induced kinase 1]; LRPPRC, [leucine-rich pentatricopeptide repeat containing protein]; TFAM, [mitochondrial transcription factor A]; PARK2, [parkin RBR E3 ubiquitin protein ligase]; and HSPA9, [heat shock protein family A (Hsp70) member 9]), 4 LRPPRC variants, (IVS32-3C>T, IVS35+14C>T, IVS35+15C>T, and IVS9+30A>G) influenced, pre-messenger RNA splicing by modulating the inclusion of the respective exons. In addition, 1-Methyl-4-phenylpyridinium ion-induced splicing changes of endogenous LRPPRC messenger RNA, reproduced the effect of the LRPPRC IVS35+14C>T mutation. Using silencing and overexpression methods, we show that LRPPRC exon 33 splicing is negatively regulated by heterogeneous nuclear ribonucleoprotein A1 both in a minigene and endogenous context. Furthermore, exon 33 exclusion due to PD-associated mutation IVS32-3C>T or heterogeneous nuclear ribonucleoprotein A1 overexpression and exon 35 exclusion due to IVS35+14C>T can be rescued by co-expression of modified U1 small nuclear RNAs, providing a potentially useful therapeutic strategy....Continue Reading

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Citations

Oct 5, 2017·Nucleic Acids Research·Lukasz GalganskiWlodzimierz J Krzyzosiak
Feb 17, 2017·Clinical Science·Diana Baralle, Emanuele Buratti
Jun 11, 2019·Frontiers in Physiology·Jie CuiHongyi Zhang

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