Mannose 6-Phosphate Receptor Is Reduced in -Synuclein Overexpressing Models of Parkinsons Disease.
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 ris...
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doaj-ed3cece4f69b467cbd97c22cb348adb62020-11-25T01:20:09ZengPublic Library of Science (PLoS)PLoS ONE1932-62032016-01-01118e016050110.1371/journal.pone.0160501Mannose 6-Phosphate Receptor Is Reduced in -Synuclein Overexpressing Models of Parkinsons Disease.Carmela MatroneNicolas DzamkoPeder MadsenMette NyegaardRegina PohlmannRikke V SøndergaardLouise B LassenThomas L AndresenGlenda M HallidayPoul Henning JensenMorten S NielsenIncreasing 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.http://europepmc.org/articles/PMC4979956?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Carmela Matrone Nicolas Dzamko Peder Madsen Mette Nyegaard Regina Pohlmann Rikke V Søndergaard Louise B Lassen Thomas L Andresen Glenda M Halliday Poul Henning Jensen Morten S Nielsen |
spellingShingle |
Carmela Matrone Nicolas Dzamko Peder Madsen Mette Nyegaard Regina Pohlmann Rikke V Søndergaard Louise B Lassen Thomas L Andresen Glenda M Halliday Poul Henning Jensen Morten S Nielsen Mannose 6-Phosphate Receptor Is Reduced in -Synuclein Overexpressing Models of Parkinsons Disease. PLoS ONE |
author_facet |
Carmela Matrone Nicolas Dzamko Peder Madsen Mette Nyegaard Regina Pohlmann Rikke V Søndergaard Louise B Lassen Thomas L Andresen Glenda M Halliday Poul Henning Jensen Morten S Nielsen |
author_sort |
Carmela Matrone |
title |
Mannose 6-Phosphate Receptor Is Reduced in -Synuclein Overexpressing Models of Parkinsons Disease. |
title_short |
Mannose 6-Phosphate Receptor Is Reduced in -Synuclein Overexpressing Models of Parkinsons Disease. |
title_full |
Mannose 6-Phosphate Receptor Is Reduced in -Synuclein Overexpressing Models of Parkinsons Disease. |
title_fullStr |
Mannose 6-Phosphate Receptor Is Reduced in -Synuclein Overexpressing Models of Parkinsons Disease. |
title_full_unstemmed |
Mannose 6-Phosphate Receptor Is Reduced in -Synuclein Overexpressing Models of Parkinsons Disease. |
title_sort |
mannose 6-phosphate receptor is reduced in -synuclein overexpressing models of parkinsons disease. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2016-01-01 |
description |
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. |
url |
http://europepmc.org/articles/PMC4979956?pdf=render |
work_keys_str_mv |
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