Journal article
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 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.
Language: | English |
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Publisher: | Public Library of Science |
Year: | 2016 |
Pages: | e0160501 |
ISSN: | 19326203 |
Types: | Journal article |
DOI: | 10.1371/journal.pone.0160501 |
ORCIDs: | 0000-0001-5819-5240 , 0000-0002-6719-0107 , 0000-0003-4973-8543 , 0000-0001-9863-9694 and Andresen, Thomas Lars |
Aged Animals Autophagy Biomarkers Brain Cathepsin D Cell Line, Tumor Disease Models, Animal Down-Regulation Female Humans Lysosomes Male Medicine Mice, Inbred C57BL Mice, Transgenic Neurons Parkinson Disease Q R RNA, Messenger Receptor, IGF Type 2 Science alpha-Synuclein trans-Golgi Network