title: Mannose 6-Phosphate Receptor Is Reduced in -Synuclein Overexpressing Models of Parkinsons Disease.
abstract: Increasing evidence points to defects in autophagy as a common denominator in most neurodegenerative conditions. Progressive functional decline in the autophagy-lysosomal pathway (ALP) occurs with age, and the consequent impairment in protein processing capacity has been associated with a higher risk of neurodegeneration. Defects in cathepsin D (CD) processing and α-synuclein degradation causing its accumulation in lysosomes are particularly relevant for the development of Parkinson's disease (PD). However, the mechanism by which alterations in CD maturation and α-synuclein degradation leads to autophagy defects in PD neurons is still uncertain. Here we demonstrate that MPR300 shuttling between endosomes and the trans Golgi network is altered in α-synuclein overexpressing neurons. Consequently, CD is not correctly trafficked to lysosomes and cannot be processed to generate its mature active form, leading to a reduced CD-mediated α-synuclein degradation and α-synuclein accumulation in neurons. MPR300 is downregulated in brain from α-synuclein overexpressing animal models and in PD patients with early diagnosis. These data indicate MPR300 as crucial player in the autophagy-lysosomal dysfunctions reported in PD and pinpoint MRP300 as a potential biomarker for PD.
authors: Department of Biomedicine, Faculty of Health, Aarhus University, 8000 Aarhus C, Denmark.
authors: Carmela
authors: C
authors: Matrone
authors: Neuroscience Research Australia, Sydney, NSW 2031, and School of Medical Sciences, Faculty of Medicine, The University of New South Wales, Sydney, NSW 2052, Australia.
authors: Nicolas
authors: N
authors: Dzamko
authors: Department of Biomedicine, Faculty of Health, Aarhus University, 8000 Aarhus C, Denmark.|Research Initiative on Blood Brain and Drug Delivery, The Lundbeck Foundation, 8000 Aarhus C, Denmark.
authors: Peder
authors: P
authors: Madsen
authors: Department of Biomedicine, Faculty of Health, Aarhus University, 8000 Aarhus C, Denmark.
authors: Mette
authors: M
authors: Nyegaard
authors: Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, 48149 Münster, Germany.
authors: Regina
authors: R
authors: Pohlmann
authors: Research Initiative on Blood Brain and Drug Delivery, The Lundbeck Foundation, 8000 Aarhus C, Denmark.|Department of Micro- and Nanotechnology, Technical University of Denmark (DTU) Nanotech, DTU, 2800 Lyngby, Denmark.
authors: Rikke V
authors: RV
authors: Søndergaard
authors: Department of Biomedicine, Faculty of Health, Aarhus University, 8000 Aarhus C, Denmark.
authors: Louise B
authors: LB
authors: Lassen
authors: Research Initiative on Blood Brain and Drug Delivery, The Lundbeck Foundation, 8000 Aarhus C, Denmark.|Department of Micro- and Nanotechnology, Technical University of Denmark (DTU) Nanotech, DTU, 2800 Lyngby, Denmark.
authors: Thomas L
authors: TL
authors: Andresen
authors: Neuroscience Research Australia, Sydney, NSW 2031, and School of Medical Sciences, Faculty of Medicine, The University of New South Wales, Sydney, NSW 2052, Australia.
authors: Glenda M
authors: GM
authors: Halliday
authors: Department of Biomedicine, Faculty of Health, Aarhus University, 8000 Aarhus C, Denmark.
authors: Poul Henning
authors: PH
authors: Jensen
authors: Department of Biomedicine, Faculty of Health, Aarhus University, 8000 Aarhus C, Denmark.|Research Initiative on Blood Brain and Drug Delivery, The Lundbeck Foundation, 8000 Aarhus C, Denmark.
authors: Morten S
authors: http://orcid.org/0000-0001-5819-5240
authors: MS
authors: Nielsen
mesh_terms: D000368:Aged; D000818:Animals; D001343:Autophagy; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002402:Cathepsin D / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017527:Receptor, IGF Type 2 / Q000235:genetics / Q000378:metabolism*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*; D021601:trans-Golgi Network / Q000378:metabolism
chemical_list: D015415:Biomarkers; D012333:RNA, Messenger; D017527:Receptor, IGF Type 2; D051844:alpha-Synuclein; D002402:Cathepsin D