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<p>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 (<i>p</i> &lt; 0.001), which correlated with disease severity. In MPP<sup>+</sup>/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. <i>Parl</i> 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 <i>Nur77</i> 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.</p><p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月6日

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  • Shiyi Yin,
  • Yibo Zhai,
  • Run Song,
  • Jiannan Wu,
  • Yongjiang Zhang,
  • Miao Yu,
  • Hongxia Ma,
  • Mengmeng Shen,
  • Xiaoyi Lai,
  • Weina Jin,
  • Yunqi Xu,
  • Junqiang Yan

摘要

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.