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 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

SUBMITTER: Qinfang Liu 

PROVIDER: S-SCDT-10_15252-EMBJ_2022113410 | biostudies-other |

REPOSITORIES: biostudies-other