biostudies-literatureUnknown16(1)Yin SParkinson'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 bindinCell death & disease700https://www.ebi.ac.uk/biostudies/studies/S-EPMC12501375biostudies-literaturePARL stabilizes mitochondrial BCL-2 via Nur77-mediated scaffolding as a therapeutic strategy for Parkinson's disease.PMC12501375Shen MLai XWu JJin WYu MYan JZhai YYin SSong RZhang YMa HXu YfalsePARL stabilizes mitochondrial BCL-2 via Nur77-mediated scaffolding as a therapeutic strategy for Parkinson's disease.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 bindin2025-01-01T00:00:00Z2025 Oct2026-06-04T05:58:37.745Z2026-05-06T03:07:48.579ZS-EPMC125013754105299910.1038/s41419-025-08035-8