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

Simona Eleuteri,Alberto Albanese

doi:10.3389/fneur.2019.01272

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.

Highlights

Parkinson’s disease (PD) is the second most common neurodegenerative disorder affecting 1% of people over 65 and 4.3% of those older than 85 [1].The clinical hallmark of PD is bradykinesia, in combination with rest tremor and rigidity [1]
vacuolar sorting protein 35 (VPS35)–D620N KI mice or knockdown or knockout of VPS35 mice impacted LRRK2-mediated Rab protein phosphorylation [44] showing that VPS35 could play a major role in controlling LRRKK2 kinase activity and supporting the hypothesis that VPS35–D620N mutation resulted in a gain of function [44]
Recent studies have been shown that Lysosome-associated membrane protein 2A (LAMP2A) receptor trafficking from endosome to Golgi is altered in mice with reduced VPS35 levels or VPS35–D620N mutations (Figure 5)

Summary

INTRODUCTION

Parkinson’s disease (PD) is the second most common neurodegenerative disorder affecting 1% of people over 65 and 4.3% of those older than 85 [1]. To evaluate the effect of VPS35–D620N mutation, a viral-mediated gene transfer model in adult rat has been developed, showing that the expression of the mutant in the nigrostriatal pathway was sufficient to induce DA neuronal loss and axonal pathology [39]. This complex represents the main sorting hub that receives, dissociates, and sorts cargoes of different origin: (i) plasma membrane (recycling of membrane receptors), (ii) biosynthetic pathways (retrieval of trafficking from Golgi), and (iii) lysosomal pathway (cargoes direct to lysosomes) [48] (Figure 3) Overall, these activities control the homeostasis of transmembrane proteins at plasma membrane and endolysosomal levels and regulate receptor abundance, signaling receptors, adhesion molecules, and hydrolase receptors

THE RETROMER COMPLEX CONTROLS SYNAPTIC FUNCTION

Findings

DISCUSSION AND OUTLOOK