VPS35-Based Approach: A Potential Innovative Treatment in Parkinson's Disease

Abstract

Several symptomatic treatments for Parkinson's disease (PD) are currently available. Still, the challenge today is to find a therapy that might reduce degeneration and slow down disease progression. The identification of pathogenic mutations in familial Parkinsonism (fPD) associated to the monogenic forms of PD provided pathophysiological insights and highlighted novel targets for therapeutic intervention. Mutations in the VPS35 gene have been associated with autosomal dominant fPD and a clinical phenotype indistinguishable from idiopathic PD. Although VPS35 mutations are relatively rare causes of PD, their study may help understanding specific cellular and molecular alterations that lead to accumulation α-synuclein in neurons of PD patients. Interacting with such mechanisms may provide innovative therapeutic approaches. We review here the evidence on the physiological role of VPS35 as a key intracellular trafficking protein controlling relevant neuronal functions. We further analyze VPS35 activity on α-synuclein degradation pathways that control the equilibrium between α-synuclein clearance and accumulation. Finally, we highlight the strategies for increasing VPS35 levels as a potential tool to treat PD.

Keywords: Parkinson's disease; alpha-synucein; amyloid protein A (AA); endosomal trafficking; retromer complex; therapeutic targets.

Figure 1

Therapeutic strategies used to reduce α-synuclein toxic aggregates accumulation in neurons. To reduce α-synuclein accumulation in neurons, several therapeutic approaches have been evaluated and tested in murine PD models: (1) antiamyloidogenic agents, such as small molecules or biocomposts to block α-synuclein aggregation and fibrillogenesis; (2) immunotherapy using α-synuclein single-chain antibody able to attenuate neuronal degeneration in vivo; (3) peptide design to block the interaction between α-synuclein oligomer and membrane, able to improve deficits in murine PD models; (4) boosting α-synuclein degradation pathways. CMA, chaperone mediated autophagy; UPS, ubiquitin proteosome system; LAMP2A, lysosome-associated membrane protein 2A.

Figure 2

VPS35 gene, protein structure and interactions. Retromer cargo recognition complex is formed by vacuolar sorting protein 26 (VPS26; 38 kDa), vacuolar sorting protein 29 (VPS29; 20 kDa), vacuolar sorting protein 35 (VPS35; 92 kDa); the dimer of sinexin (SNXs). The N-terminal region (in blue) from the amino acid residues 1 to 172 [1–172] and C-terminal region (violet) from 307 to 796 (307–796) are important, respectively, for the interaction with VPS26 and VPS29 (36). The amino acid residues involved in the interaction with the SNXs are at N-terminal region (–, –54) and C-terminal region (307–796). A structural level VPS35 is a right-handed α-helix solenoid, and it is predicted to have 34 helices, 13 of which are in C-terminal. Different missense mutations have been identified in fPD. VPS35 variant of uncertain significance (VUS) are localized between exon 9 (P316S), exon 13 (R542W), and exon 14 (I560T, H599R, M607V), and the confirmed pathogenic mutation (D620N) is localized on the exon 15 (genes in light violet).

Figure 3

Retromer complex functions. Retromer complex (in green) controls the sorting of cargoes (1) originate from plasma membrane (receptors in red), (2) direct to lysosome for degradation, and (3) trafficking between trans-Golgi Network (TGN) (3, 4). Figure was adapted from Servier Medical Art images (http://smart.servier.com/).

Figure 4

α-Synuclein degradation pathways in cells. Toxic aggregates of α-synuclein can be degraded in the cells through three pathways: macroautophagy (1), endosomal system (2), and chaperone-mediated autophagy (CMA) (3). (1) In the autophagy, key molecules can lead the autophagosome formation and the degradation of aggregates of α-synuclein; (2) lysosomal hydrolases generated in trans-Golgi Network (TGN) are sorted from specific hydrolase sorting receptors [cation-independent 6 mannose phosphate receptor (CI-MPR) and Sortilin], through the endosomal system to the lysosome, and mediate α-synuclein degradation; (3) chaperone-dependent selection of soluble α-synuclein aggregates that are targeted to lysosomes and directly translocated across the lysosomal membrane for degradation. Figure was adapted from Servier Medical Art images (http://smart.servier.com/).

Figure 5

VPS35-retromer subunit controls the main α-synuclein degradation pathways. VPS35 has a relevant role in controlling the degradation of key molecules in the α-synuclein degradation pathways. In the autophagic process, vacuolar sorting protein 35 (VPS35) interacts and controls the trafficking of Wiskott–Aldrich syndrome protein (WASH) complex (blue) and autophagy-related protein 9A (ATG9A; blue) assuring the correct autophagosome formation; in chaperone-mediated autophagy (CMA), VPS35 controls the retrieval trafficking of lysosome-associated membrane protein 2A (LAMP2A) receptor (light green) to the trans-Golgi Network (TGN); VPS35 interacts with CI-MPR (dark green) and Sortilin (pink) leading indirectly to the trafficking of cathepsin D (CTSD, in red) through early endosomes (EE) and late endosomes (LE). VPS35–D620N mutation and VPS35 deficiency lead to dysfunctions in α-synuclein degradation. Figure was adapted from Servier Medical Art images (http://smart.servier.com/).

Figure 6

VPS35 deficiency and dopamine (DA) neuronal loss. VPS35-retromer subunit controls different mechanisms in the cells as well as synaptic and mitochondrial functions other than dopamine transporter (DAT) recycling and α-synuclein degradation. Altogether, the data give an overview about the possible molecular mechanisms controlled by vacuolar protein sorting 35 (VPS35), which could lead to DA neuron degeneration in Parkinson's disease (PD). Figure was adapted from Servier Medical Art images (http://smart.servier.com/).