VPS35 regulates parkin substrate AIMP2 toxicity by facilitating lysosomal clearance of AIMP2

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.

Alpha-Synuclein Physiology and Pathology: A Perspective on Cellular Structures and Organelles

“…Another molecule that may promote α-syn accumulation is vacuolar protein sorting-associated protein 35 (VPS35). VPS35 is a component of the retromer complex involved in the transport of the endosome to the TGN, the membrane protein retrieval, the endosomal recycling (Yun et al, 2017), and a rare form of autosomal-dominant parkinsonism (Vilariño-Güell et al, 2011). It has been shown in mice with a VPS35 deletion that oligomeric and phosphorylated α-syn is increased.…”

Cellular and Molecular Basis of Neurodegeneration in Parkinson Disease

“…VPS35 mutant D620N disrupted the interaction of VPS35 with aminoacyl tRNA synthetase complex-interacting multifunctional protein 2 (AIMP2), a Parkin substrate, and lysosome-associated membrane protein-2a (LAMP2A). Overexpression of VPS35 inhibited AIMP2-enhanced cell death in SH-SY5Y cells; In contrast, downregulation of VPS35 resulted in AIMP2 dependent-cell death ( Yun et al, 2017 ). VPS35-deficient DA neurons exhibit impaired endosome-to-Golgi retrieval of Lamp2a, which may contribute to the reduced α-synuclein degradation through chaperone-mediated autophagy ( Tang et al, 2015a ).…”

The genetic architecture of mitochondrial dysfunction in Parkinson’s disease

“…For VPS35 harbouring the PD-associated D620N mutation, this association was disturbed and led to an increased level of non-degraded AIMP2, which translocates to nucleus and activates PARP1 leading to cell death (Yun et al 2017; Lee et al 2013). …”

“…VPS35 also has an anti-apoptotic role via its association with Lamp2a and with the Parkin substrate, aminoacyl-tRNA synthetase complex interacting multifunctional protein-2 (AIMP2) (Yun et al 2017 ). For VPS35 harbouring the PD-associated D620N mutation, this association was disturbed and led to an increased level of non-degraded AIMP2, which translocates to nucleus and activates PARP1 leading to cell death (Yun et al 2017 ; Lee et al 2013 ).…”