title: New roles of glycosaminoglycans in α-synuclein aggregation in a cellular model of Parkinson disease.
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.
authors.affiliation: Université Paris-Est Créteil, Laboratoire CRRET-EAC CNRS 7149, 61 Avenue de Général de Gaulle, 94010, Créteil, France.
authors.forename: Sonia
authors.initials: S
authors.lastname: Lehri-Boufala
authors.affiliation: Université Paris-Est Créteil, Laboratoire CRRET-EAC CNRS 7149, 61 Avenue de Général de Gaulle, 94010, Créteil, France.
authors.forename: Mohand-Ouidir
authors.initials: MO
authors.lastname: Ouidja
authors.affiliation: Université Paris-Est Créteil, Laboratoire CRRET-EAC CNRS 7149, 61 Avenue de Général de Gaulle, 94010, Créteil, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Barbier-Chassefière
authors.affiliation: Université Paris-Est Créteil, Laboratoire CRRET-EAC CNRS 7149, 61 Avenue de Général de Gaulle, 94010, Créteil, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Hénault
authors.affiliation: CNRS UMR 7225, Hôpital de la Salpêtrière-Bâtiment, ICM (Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière), CRICM, Thérapeutique Expérimentale de la Neurodégénérescence, Université Pierre et Marie Curie, UPMC, 75651, Paris, France.
authors.forename: Rita
authors.initials: R
authors.lastname: Raisman-Vozari
authors.affiliation: Université Paris-Est Créteil, Laboratoire CRRET-EAC CNRS 7149, 61 Avenue de Général de Gaulle, 94010, Créteil, France.
authors.forename: Laure
authors.initials: L
authors.lastname: Garrigue-Antar
authors.affiliation: Université Paris-Est Créteil, Laboratoire CRRET-EAC CNRS 7149, 61 Avenue de Général de Gaulle, 94010, Créteil, France.
authors.forename: Dulce
authors.initials: D
authors.lastname: Papy-Garcia
authors.affiliation: Université Paris-Est Créteil, Laboratoire CRRET-EAC CNRS 7149, 61 Avenue de Général de Gaulle, 94010, Créteil, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Morin
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology; D000595:Amino Acid Sequence; D017209:Apoptosis / Q000187:drug effects; D002402:Cathepsin D / Q000378:metabolism; D045744:Cell Line, Tumor; D006025:Glycosaminoglycans / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology*; D066329:Protein Aggregates / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D051844:alpha-Synuclein / Q000737:chemistry* / Q000378:metabolism
chemical_list: D006025:Glycosaminoglycans; D066329:Protein Aggregates; D051844:alpha-Synuclein; D002402:Cathepsin D; D015655:1-Methyl-4-phenylpyridinium