Study summary · research use only
Regulation of LRRK2 mRNA stability by ATIC and its substrate AICAR through ARE-mediated mRNA decay in Parkinson's disease
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
This in vitro and mouse/Drosophila study investigated how the purine biosynthesis enzyme ATIC and its substrate precursor AICAr regulate LRRK2 protein levels, which are linked to Parkinson's disease. The authors report that AICAr regulates LRRK2 levels in a cell-type-specific manner in vitro and in mouse tissue, acting through AUF1-mediated decay of LRRK2 mRNA after AUF1 is recruited to AU-rich elements and the DCP1/2 decapping complex is engaged. AICAr treatment reduced LRRK2 expression and reduced LRRK2-induced dopaminergic neurodegeneration and neuroinflammation in Parkinson's disease Drosophila and mouse models. The study describes this as a regulatory mechanism distinct from LRRK2's own enzymatic activity.
Abstract
Mutations in LRRK2 are the most common genetic causes of Parkinson's disease (PD). While the enzymatic activity of LRRK2 has been linked to PD, previous work has also provided support for an important role of elevated LRRK2 protein levels, independent of enzymatic activity, in PD pathogenesis. However, the mechanisms underlying the regulation of LRRK2 protein levels remain unclear. Here, we identify a role for the purine biosynthesis pathway enzyme ATIC in the regulation of LRRK2 levels and toxicity. AICAr, the precursor of ATIC substrate, regulates LRRK2 levels in a cell-type-specific manner in vitro and in mouse tissue. AICAr regulates LRRK2 levels through AUF1-mediated mRNA decay. Upon AICAr treatment, the RNA binding protein AUF1 is recruited to the AU-rich elements (ARE) of LRRK2 mRNA leading to the recruitment of the decapping enzyme complex DCP1/2 and decay of LRRK2 mRNA. AICAr suppresses LRRK2 expression and rescues LRRK2-induced dopaminergic neurodegeneration and neuroinflammation in PD Drosophila and mouse models. Together, this study provides insight into a novel regulatory mechanism of LRRK2 protein levels and function via LRRK2 mRNA decay that is distinct from LRRK2 enzymatic functions.
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