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<p>Heterozygous (G603R) LRP10 mutation causes autosomal dominant Parkinson’s disease (PD). Heterozygous Lrp10<sup>G603R/+</sup> mice were prepared to unravel pathomechanisms underlying (G603R) Lrp10-induced death of substantia nigra (SN) dopaminergic neurons. Lrp10<sup>G603R/+</sup> mouse exhibited PD movement deficits, neurodegeneration of SN dopaminergic cells and existence of SN phospho-α-synuclein-containing aggregates. Lrp10 was expressed in mouse SN dopaminergic neurons, and WT LRP10 exerted neuroprotection function on dopaminergic cells by repressing α-synuclein gene transcription and downregulating α-synuclein mRNA. (G603R) LRP10 failed to negatively regulate α-synuclein mRNA of dopaminergic neurons, and heterozygous (G603R) Lrp10 mutation elevated protein and mRNA of pathological α-synuclein or α-synuclein oligomers in SN dopaminergic cells of Lrp10<sup>G603R/+</sup> mouse. Macroautophagy activator rapamycin reversed (G603R) Lrp10-induced increment of α-synuclein, death of SN dopaminergic cells and PD locomotor disability in Lrp10<sup>G603R/+</sup> mouse. (G603R) Lrp10 upregulation of α-synuclein increased ER α-synuclein and activated ER stress and UPR, resulting in excitation of ER stress pro-apoptotic pathway in SN of Lrp10<sup>G603R/+</sup> mouse. Upregulated α-synuclein within SN dopaminergic cells increased mitochondrial α-synuclein and induced mitochondrial detriment and oxidative insult in SN of Lrp10<sup>G603R/+</sup> mouse. (G603R) Lrp10-evoked overexpression of Puma, Noxa or Bim and mitochondrial abnormality excited mitochondrial apoptotic process in SN of Lrp10<sup>G603R/+</sup> mouse. Elevated α-synuclein oligomers excited NLRP3 inflammasome and microglia in SN of Lrp10<sup>G603R/+</sup> mouse, leading to incremented IL-1β-, IL-18- or TNF-α-triggered MKK4-JNK-c-Jun/ATF-2 degeneration and RIPK1-RIPK3-MLKL necroptotic pathways. Our data propose that heterozygous loss-of-function (G603R) mutation of LRP10 debilitates WT LRP10-mediated downregulation of α-synuclein mRNA, leading to elevated α-synuclein-evoked neurodegeneration of SN dopaminergic cells and autosomal dominant PD.</p>

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Loss-of-Function (G603R) Lrp10 Fails to Downregulate mRNA of Pathologic α-Synuclein and Causes Neurodegeneration of Substantia Nigra Dopaminergic Cells in Parkinson’s Disease Knockin Mice

  • 期刊论文

  • 发表日期：

    2026年5月20日

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  • Hung-Li Wang,
  • Shu-Yu Liu,
  • Ching-Chi Chiu,
  • Tu-Hsueh Yeh,
  • Wan-Shia Chen,
  • Tai-Ju Chiu,
  • Yi-Chun Yeh,
  • Pei-Rung Wu,
  • Yi-Hsin Weng

摘要

Heterozygous (G603R) LRP10 mutation causes autosomal dominant Parkinson’s disease (PD). Heterozygous Lrp10G603R/+ mice were prepared to unravel pathomechanisms underlying (G603R) Lrp10-induced death of substantia nigra (SN) dopaminergic neurons. Lrp10G603R/+ mouse exhibited PD movement deficits, neurodegeneration of SN dopaminergic cells and existence of SN phospho-α-synuclein-containing aggregates. Lrp10 was expressed in mouse SN dopaminergic neurons, and WT LRP10 exerted neuroprotection function on dopaminergic cells by repressing α-synuclein gene transcription and downregulating α-synuclein mRNA. (G603R) LRP10 failed to negatively regulate α-synuclein mRNA of dopaminergic neurons, and heterozygous (G603R) Lrp10 mutation elevated protein and mRNA of pathological α-synuclein or α-synuclein oligomers in SN dopaminergic cells of Lrp10G603R/+ mouse. Macroautophagy activator rapamycin reversed (G603R) Lrp10-induced increment of α-synuclein, death of SN dopaminergic cells and PD locomotor disability in Lrp10G603R/+ mouse. (G603R) Lrp10 upregulation of α-synuclein increased ER α-synuclein and activated ER stress and UPR, resulting in excitation of ER stress pro-apoptotic pathway in SN of Lrp10G603R/+ mouse. Upregulated α-synuclein within SN dopaminergic cells increased mitochondrial α-synuclein and induced mitochondrial detriment and oxidative insult in SN of Lrp10G603R/+ mouse. (G603R) Lrp10-evoked overexpression of Puma, Noxa or Bim and mitochondrial abnormality excited mitochondrial apoptotic process in SN of Lrp10G603R/+ mouse. Elevated α-synuclein oligomers excited NLRP3 inflammasome and microglia in SN of Lrp10G603R/+ mouse, leading to incremented IL-1β-, IL-18- or TNF-α-triggered MKK4-JNK-c-Jun/ATF-2 degeneration and RIPK1-RIPK3-MLKL necroptotic pathways. Our data propose that heterozygous loss-of-function (G603R) mutation of LRP10 debilitates WT LRP10-mediated downregulation of α-synuclein mRNA, leading to elevated α-synuclein-evoked neurodegeneration of SN dopaminergic cells and autosomal dominant PD.