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

  • Neurochem Res. 2026 May 20;51(3):162. doi: 10.1007/s11064-026-04762-2.
Hung-Li Wang  1  2  3  4 ,  Shu-Yu Liu  1 ,  Ching-Chi Chiu  3  4  5 ,  Tu-Hsueh Yeh  6 ,  Wan-Shia Chen  1 ,  Tai-Ju Chiu  7 ,  Yi-Chun Yeh  1 ,  Pei-Rung Wu  1 ,  Yi-Hsin Weng  8  9  10
Affiliations
  • 1. Department of Physiology and Pharmacology, Chang Gung University College of Medicine, Taoyuan, Taiwan.
  • 2. Division of Movement Disorders, Department of Neurology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan.
  • 3. Healthy Aging Research Center, Chang Gung University College of Medicine, Taoyuan, Taiwan.
  • 4. Neuroscience Research Center, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan.
  • 5. Department of Medical Biotechnology and Laboratory Science, Chang Gung University College of Medicine, Taoyuan, Taiwan.
  • 6. Department of Neurology, Taipei Medical University Hospital, Taipei, Taiwan.
  • 7. Graduate Institute of Biomedical Sciences, Chang Gung University College of Medicine, Taoyuan, Taiwan.
  • 8. Division of Movement Disorders, Department of Neurology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan. [email protected].
  • 9. Neuroscience Research Center, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan. [email protected].
  • 10. College of Medicine, Chang Gung University, Taoyuan, Taiwan. [email protected].
PMID: 42159631 DOI: 10.1007/s11064-026-04762-2
Abstract

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.

Keywords
(G603R) LRP10 mutation; Autosomal dominant Parkinson’s disease; Lrp10G603R/+ knockin mouse; Substantia nigra dopaminergic neurons; α-Synuclein mRNA.
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