Abstract
Vacuolar protein sorting-associated protein 35 (VPS35) is involved in retrograde transport of proteins from endosomes to trans-Golgi network. Gene mutations in VPS35 are linked to autosomal dominant late-onset Parkinson’s disease (PD). Although the identification of VPS35 mutations has provided novel insight about its interactions with several PD-associated genes including leucine-rich repeat kinase 2 (LRRK2) and α-synuclein, little information is available about the molecular mechanisms of cell death downstream of VPS35 dysfunction. In this study, we showed that VPS35 has a role in the lysosomal degradation of parkin substrate aminoacyl tRNA synthetase complex-interacting multifunctional protein 2 (AIMP2), of which accumulation leads to poly(ADP-ribose) polymerase-1 (PARP1)-dependent cell death. VPS35 was co-immunoprecipitated with AIMP2, as well as lysosome-associated membrane protein-2a (Lamp2a). Interestingly, this association was disrupted by PD-associated VPS35 mutant D620N. VPS35 overexpression prevented AIMP2-potentiated cell death and PARP1 activation in SH-SY5Y cells. More importantly, knockdown of VPS35 led to PARP1 activation and cell death, which was AIMP2 dependent. These findings provide new mechanistic insights into the role of VPS35 in the regulation of AIMP2 levels and cell death. As AIMP2 accumulation was reported in PD patient’s brains and involved in dopaminergic cell death, identification of VPS35 as a novel regulator of AIMP2 clearance via lysosomal pathway provides alternative venue to control dopaminergic cell death in PD.
Highlights
Degeneration of midbrain dopaminergic neurons contributes to cardinal motor deficits in Parkinson’s disease (PD)
Aminoacyl tRNA synthetase complex-interacting multifunctional protein 2 (AIMP2) is a pathogenic parkin substrate that accumulates in animal models of parkin inactivation and postmortem PD patient brains.[9,10]
To identify the potential role of VPS35 in regulating pathogenic parkin substrate AIMP2, we performed a small-scale screening in SH-SY5Y cells transiently transfected with V5-WT VSP35 or the PD-linked mutant version V5-D620N VPS35
Summary
Degeneration of midbrain dopaminergic neurons contributes to cardinal motor deficits in Parkinson’s disease (PD). Cell Death and Disease proteins, endosomal recycle and others.[15,16,17] Interestingly, VPS35 downregulation is clinically associated with neurodegenerative diseases including PD and Alzheimer’s disease (AD).[18,19] Consistent with this notion, VPS35 ablation in dopaminergic neurons results in PD-associated deficits in mice, such as α-synuclein accumulation, loss of dopamine neurons and motor impairment.[20,21] Absence of VPS35 renders yeast more vulnerable to protein aggregationinduced toxicity by eukaryotic translation initiation factor 4 gamma 1 (EIF4G1) overexpression.[22] overexpression of WT VPS35 rescues locomotor deficits and reduction of lifespan in leucine-rich repeat kinase 2 (LRRK2) transgenic PD fly models.[23] VPS35 protects neurons against mitochondrial toxin 1-methyl-4-phenylpyridinium (MPP+)-induced oxidative stress.[24] Dysfunction of VPS35 by reduction of its expression levels or PD-linked mutations results in abnormal recycling or subcellular targeting of its substrates.[17,20,25] For instance, VPS35 deficits lead to abnormal delivery of lysosome proteases because of defective targeting of cation-independent mannose 6-phosphate receptor, a cargo of VPS35/retromer.[17,25] It has been shown that impaired endosome-to-golgi retrieval of lysosomeassociated membrane glycoprotein-2a (Lamp2a) is responsible for lysosomal degradation of available Lamp2a pool in dopamine neurons of VPS35 deletion.[20] As Lamp2a mediates α-synuclein degradation via chaperone-mediated autophagy (CMA), downregulation of lamp2a following VPS35 deficits can lead to accumulation of α-synuclein.[20]. Our finding provided a novel pathway of AIMP2 degradation that could be used to control AIMP2 accumulation and dopaminergic cell death in PD
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