New roles of glycosaminoglycans in α-synuclein aggregation in a cellular model of Parkinson disease.

Sonia Lehri-Boufala,Emilie Hénault,Laure Garrigue-Antar,Rita Raisman-Vozari,Christophe Morin,Dulce Papy-Garcia,Mohand-Ouidir Ouidja,Véronique Barbier-Chassefière,Thomas Arendt

doi:10.1371/journal.pone.0116641

Abstract

The causes of Parkinson disease (PD) remain mysterious, although some evidence supports mitochondrial dysfunctions and α-synuclein accumulation in Lewy bodies as major events. The abnormal accumulation of α-synuclein has been associated with a deficiency in the ubiquitin-proteasome system and the autophagy-lysosomal pathway. Cathepsin D (cathD), the major lysosomal protease responsible of α-synuclein degradation was described to be up-regulated in PD model. As glycosaminoglycans (GAGs) regulate cathD activity, and have been recently suggested to participate in PD physiopathology, we investigated their role in α-synuclein accumulation by their intracellular regulation of cathD activity. In a classical neuroblastoma cell model of PD induced by MPP+, the genetic expression of GAGs-biosynthetic enzymes was modified, leading to an increase of GAGs amounts whereas intracellular level of α-synuclein increased. The absence of sulfated GAGs increased intracellular cathD activity and limited α-synuclein accumulation. GAGs effects on cathD further suggested that specific sequences or sulfation patterns could be responsible for this regulation. The present study identifies, for the first time, GAGs as new regulators of the lysosome degradation pathway, regulating cathD activity and affecting two main biological processes, α-synuclein aggregation and apoptosis. Finally, this opens new insights into intracellular GAGs functions and new fields of investigation for glycobiological approaches in PD and neurobiology.

Highlights

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases affecting almost 1% of the population worldwide and is mainly characterized by the death of dopaminergic neurons in the substantia nigra
Co-localization of cathepsin D, glycosaminoglycans and α-synuclein in MPP+-stressed cells.As regulation of cathD by GAGs through their sulfation pattern was suggested to modulate α-synuclein accumulation/degradation (Figs. 2, 5, 6) we investigated whether they could co-localize in cells
Substantial amount of evidence suggests that the oligomerisation of α-synuclein followed by its aggregation is a critical step in the etiology of PD [32, 33]

Summary

Introduction

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases affecting almost 1% of the population worldwide and is mainly characterized by the death of dopaminergic neurons in the substantia nigra. GAGs extracted from stressed by MPP+ or normal neuroblastoma cells were incubated with commercial cathD (0.5 mM) during 1 h at 37°C in presence of specific substrate and the fluorescence was measured as previously described.

Results

Conclusion