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Journal Articles PLoS ONE Year : 2015

New Roles of Glycosaminoglycans in α-Synuclein Aggregation in a Cellular Model of Parkinson Disease

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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 neu-roblastoma 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 ag-gregation and apoptosis. Finally, this opens new insights into intracellular GAGs functions and new fields of investigation for glycobiological approaches in PD and neurobiology.
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hal-01235737 , version 1 (30-11-2015)

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Attribution - CC BY 4.0

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Sonia Lehri-Boufala, Mohand-Ouidir Ouidja, Véronique Barbier-Chassefière, Emilie Hénault, Rita Raisman-Vozari, et al.. New Roles of Glycosaminoglycans in α-Synuclein Aggregation in a Cellular Model of Parkinson Disease. PLoS ONE, 2015, 10 (1), pp.e0116641. ⟨10.1371/journal.pone.0116641⟩. ⟨hal-01235737⟩
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