Lrp10 insufficiency upregulates mRNA and protein of neurotoxic α-synuclein and causes degeneration of substantia nigra dopaminergic neurons in heterozygous or homozygous Lrp10 knockout mice.

Heterozygous intronic mutations of LRP10 (low density lipoprotein receptor-related protein 10) gene, which produce LRP10 haploinsufficiency by impairing splicing of LRP10 mRNA and generating loss-of-function truncated LRP10, cause autosomal dominant Parkinson's disease (PD). Heterozygous Lrp10+/- knockout mice, which replicate heterozygous intronic mutation of LRP10-induced LRP10 haploinsufficiency, and homozygous Lrp10-/- knockout mice were utilized to elucidate molecular pathomechanisms underlying Lrp10 insufficiency-triggered demise of substantia nigra pars compacta (SNpc) dopaminergic neurons. Lrp10+/- and Lrp10-/- knockout mice displayed PD motor impairment, neurodegeneration of SNpc dopaminergic cells and presence of SN phospho-α-synuclein-containing Lewy bodies. Lrp10 was expressed in mouse SNpc dopaminergic neurons. WT LRP10 downregulated α-synuclein mRNA, and Lrp10 deficiency elevated α-synuclein mRNA via augmenting transcription of α-synuclein gene in dopaminergic neurons. Lrp10 deficiency-induced elevation of α-synuclein mRNA upregulated pathological α-synuclein and α-synuclein oligomers within SNpc dopaminergic neurons of Lrp10+/- or Lrp10-/- mice. Macroautophagy activator rapamycin prevented Lrp10 paucity-induced upregulation of SN α-synuclein, PD neurological and neuropathological phenotypes observed in Lrp10+/- or Lrp10-/- knockout mice. Lrp10 insufficiency-induced upregulation of ER and mitochondrial α-synuclein stimulated ER stress and mitochondrial apoptotic cascades in SN of Lrp10+/- or Lrp10-/- mice. Lrp10 paucity-evoked elevation of pathologic α-synuclein oligomers activated microglia and NLRP3 inflammasome and upregulated TNF-α, IL-1β and IL-18, which excited RIPK1-RIPK3-MLKL necroptotic pathway and MKK4-JNK -c-Jun/ATF-2 apoptotic signaling in SN of Lrp10+/- or Lrp10-/- knockout mice. Our results suggest that heterozygous intronic mutation of LRP10-induced LRP10 haploinsufficiency causes degeneration of SNpc dopaminergic neurons and autosomal dominant PD by upregulating mRNA and protein of neurotoxic α-synuclein.