Regulation of LRRK2 mRNA stability by ATIC and its substrate AICAR through ARE‐mediated mRNA decay in Parkinson's disease

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 celltype-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 AUrich 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.

In-depth mass-spectrometry reveals phospho-RAB12 as a blood biomarker of G2019S LRRK2-driven Parkinson’s

“…2). We found that in G2019S L2PD a number of proteins expression was reduced namely, ATIC, which can repress LRRK2 and rescue neurodegeneration 48 (log2FC=-0.97, adj. P=1.92x10 -13 ); RAB9A, involved in phagocytic vesicle trafficking and lysosomal function (log2FC=-1.17, adj.…”

“…61 Thus, ATIC, the top protein down-regulated in G2019S carriers, catalyses the last two steps of mitochondria purine biosynthesis 62,63 and was also linked previously to LRRK2 toxicity. 48 Other deficits included KARS1, a tRNA synthetase; PSMC5, the proteasomal 26S subunit; or SCLY, seleno-cysteine lyase, an enzyme involved in peptide elongation that is also involved in neurodegeneration. 64 Our findings in LRRK2 PMBCs align with studies reporting transcriptional repression of proteostasis regulators in G2019S L2PD, 65 and proteostasis defects in PD substantia nigra.…”