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

Area of Science:

• Genetics
• Molecular Biology
• Neuroscience

Background:

• Parkinson's disease (PD) is a neurodegenerative disorder with a genetic component.
• Splicing alterations in key genes are increasingly recognized as contributors to PD pathogenesis.
• Understanding the functional impact of PD-associated genetic variants on RNA splicing is crucial for elucidating disease mechanisms.

Purpose of the Study:

• To investigate the impact of Parkinson's disease-associated genetic variants on pre-messenger RNA splicing.
• To identify specific variants and genes involved in splicing dysregulation in PD.
• To explore potential therapeutic strategies for PD by correcting splicing defects.

Main Methods:

• Utilized dedicated minigene assays to analyze splicing.
• Investigated 14 putative splicing variants in 5 PD-associated genes (PINK1, LRPPRC, TFAM, PARK2, HSPA9).
• Employed gene silencing and overexpression techniques, including heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) and modified U1 small nuclear RNAs (snRNAs).

Main Results:

• Four variants in the leucine-rich pentatricopeptide repeat containing protein (LRPPRC) gene (IVS32-3C>T, IVS35+14C>T, IVS35+15C>T, IVS9+30A>G) were found to influence pre-messenger RNA splicing.
• 1-Methyl-4-phenylpyridinium ion exposure mimicked the splicing effects of the LRPPRC IVS35+14C>T mutation on endogenous LRPPRC.
• LRPPRC exon 33 splicing is negatively regulated by hnRNP A1; splicing defects can be rescued by modified U1 snRNAs.

Conclusions:

• LRPPRC intronic variants can disrupt normal gene splicing, potentially influencing Parkinson's disease risk.
• hnRNP A1 plays a regulatory role in LRPPRC splicing.
• Modified U1 snRNAs represent a potential therapeutic avenue for PD by rescuing splicing abnormalities.