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

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

  • Cell Death Dis. 2025 Oct 6;16(1):700. doi: 10.1038/s41419-025-08035-8.
Shiyi Yin 1,  Yibo Zhai 1,  Run Song 1,  Jiannan Wu 1,  Yongjiang Zhang 1,  Miao Yu 1,  Hongxia Ma 1,  Mengmeng Shen 1,  Xiaoyi Lai 1,  Weina Jin 2,  Yunqi Xu 3,  Junqiang Yan 4 5
Affiliations

Affiliations

  • 1 Key Laboratory of Neuromolecular Biology, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China.
  • 2 China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
  • 3 Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
  • 4 Key Laboratory of Neuromolecular Biology, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China. yanjq@haust.edu.cn.
  • 5 Department of Neurology, The First Affiliated Hospital, College of Clinical Medi-cine of Henan University of Science and Technology, Luoyang, China. yanjq@haust.edu.cn.
PMID: 41052999 DOI: 10.1038/s41419-025-08035-8
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 binding. Disrupting this interface abolished Bcl-2 stabilization. Parl knockdown exacerbated motor/cognitive deficits in MPTP mice, rescued by Nur77 overexpression. Subcellular tracking demonstrated Nur77 nuclear-cytoplasmic shuttling dynamically regulates PARL-BCL-2 assembly, while co-immunoprecipitation confirmed Nur77 knockdown dissociates this complex. Our findings define the Nur77-PARL axis as a critical mitochondrial gatekeeper in PD, where PARL serves dual roles as a Lewy body constituent and Apoptosis regulator. Reduced circulating PARL levels may reflect disease progression, while the Nur77-PARL structural interface offers a therapeutic target for neuroprotection. This study bridges Lewy body biology with mitochondrial Apoptosis. It proposes biomarker-driven strategies to modulate BCL-2-dependent neuronal survival in PD. Schematic summary. In normal neuronal cells, PARL can inhibit the release of apoptotic signals by interacting with Nur77. In the MPP+-induced PD model, PARL expression is reduced inhibits the Apoptosis of dopaminergic neurons, and reduces cell viability. Mechanistic schema: Normal state: PARL-Nur77 complex stabilizes mitochondrial membrane integrity, inhibiting Bcl-2 ubiquitination. MPP+ injury: PARL downregulation disrupts Nur77 binding, triggering Bax oligomerization and Caspase-3 activation. Therapeutic rescue: Nur77 overexpression restores PARL-mediated anti-apoptotic signaling.

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