PARL stabilizes mitochondrial BCL-2 via Nur77-mediated scaffolding as a therapeutic strategy for Parkinson's disease.

ABSTRACT: Parkinson's disease (PD) involves both mitochondrial dysfunction and Lewy body pathology. However molecular links between these features remain unclear. Here, we identify Presenilin-associated rhomboid-like protein (PARL) as a Lewy body component, RARL regulates mitochondrial apoptosis via interacting with orphan nuclear receptor Nur77. Clinical profiling revealed reduced plasma PARL levels in 71 PD patients versus controls (p < 0.001), which correlated with disease severity. In MPP⁺/MPTP models, PARL depletion amplified BAX activation and caspase-3 cleavage, driving neuronal death. Mechanistically, mitochondrial translocation of Nur77 stabilized PARL-BCL-2 complexes, suppressing apoptosis. AlphaFold2-guided structural modeling uncovered a PARL α-helix essential for Nur77 bindin

SUBMITTER: Yin S 

PROVIDER: S-EPMC12501375 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature