An update on cellular and molecular determinants of Parkinson's disease with emphasis on the role of the retromer complex

Abstract

Parkinson's disease (PD) is a highly prevalent neurodegenerative condition. The disease involves the progressive degeneration of dopaminergic neurons located in the substantia nigra pars compacta. Among late‐onset, familial forms of Parkinson are cases with mutations in the PARK17 locus encoding the vacuolar protein sorting 35 (Vps35), a subunit of the retromer complex. The retromer complex is composed of a heterotrimeric protein core (Vps26‐Vps35‐Vps29). The best‐known role of retromer is the retrieval of cargoes from endosomes to the Golgi complex or the plasma membrane. However, recent literature indicates that retromer performs roles associated with lysosomal and mitochondrial functions and degradative pathways such as autophagy. A common point mutation affecting the retromer subunit Vps35 is D620N, which has been linked to the alterations in the aforementioned cellular processes as well as with neurodegeneration. Here, we review the main aspects of the malfunction of the retromer complex and its implications for PD pathology. Besides, we highlight several controversies still awaiting clarification.

VPS34-dependent control of apical membrane function of proximal tubule cells and nutrient recovery by the kidney

“…We found grossly mislocalized and non–membrane-associated GAL-3 in Vps34 −/− PT cells, a finding likely incompatible with finely tuned PT function ( 54 ). Similarly, we observed alterations in the retromer complex, a cargo selection machinery for retrograde trafficking pathways and plasma membrane recycling ( 55 , 56 ). This complex is controlled by VPS34 in yeast and Caenorhabditis elegans ( 57 , 58 ).…”

Retromer dependent changes in cellular homeostasis and Parkinson's disease

“…Recently it has been directly demonstrated the Vps35 D620N variant is deficient in the formation of retrograde ETC ( Figure 1 ) [ 48 ]. However, the molecular mechanisms underpinning this defect in protein trafficking are not fully determined [ 49 ]. In vitro isothermal titration calorimetry and affinity immunoprecipitation experiments clearly demonstrate that Vps35 D620N variant has no effect on assembly of the retromer core trimer formation [ 50 , 51 ].…”

Sorting nexins: role in the regulation of blood pressure

“…The most basic role of SNXs is being a vital constituent of the retromer [28][29][30]. The retromer is a heteropentameric complex composed of two associated but distinct subcomplexes: a membrane-associated SNX dimeric subcomplex and a heterotrimer that includes VPS26, VPS29, and VPS35 [28].…”

“…The retromer is a heteropentameric complex composed of two associated but distinct subcomplexes: a membrane-associated SNX dimeric subcomplex and a heterotrimer that includes VPS26, VPS29, and VPS35 [28]. The retromer core complex is an endosomal scaffold that mediates the recycling or trafficking of intracellular proteins, such as G protein-coupled receptors and other cargos from endosomes to either the trans-Golgi network or the plasma membrane [29,30]. The retromer interacts with three SNX subfamily members, including SNX3 from the SNX-PX subfamily, SNX-BAR subfamily members, and SNX27 from the SNX-FERM subfamily.…”