Brain neuronal CG9593/ANGPTL4 activation mediates paternally acquired motor disorders

Recently, the perspective of paternal origin has emerged, yet its role in motor disorders remains unclear. Here, using <i>Drosophila</i> and murine models, we demonstrated that following paternal environmental heavy metal stress, offspring from multiple generations exhibited progressive motor deficits accompanied by dopaminergic neuron loss. Cross-tissue RNA sequencing revealed dysregulation of CG9593 (functionally homologous to human angiopoietin-like protein 4, ANGPTL4), identifying CG9593/ANGPTL4 as a pivotal brain effector linking paternal heavy metal stress to multigenerational motor disorders across species. Specifically, neuron-specific <i>CG9593</i> knockdown ameliorated these disorders, whereas <i>CG9593</i> overexpression mimicked them. Mechanistically, N6-methyladenosine (m6A) hypermethylation in sperm stabilized <i>CG9593</i> messenger RNA in offspring neurons via IGF2BP1-dependent posttranscriptional regulation, reducing synapse-associated protein DLG1 and impairing motor neuron. Human cohort analyses confirmed that serum ANGPTL4 negatively correlated with pediatric motor scores, and paternal sperm m6A levels were positively associated with the heavy metal exposure burden. Our findings establish CG9593/ANGPTL4 as an evolutionarily conserved determinant of paternally acquired multigenerational motor disorders and hold promise as a druggable target.