期刊
PLOS ONE
卷 11, 期 8, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0160501
关键词
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资金
- Danish Council [4004-00330B/FSS]
- Lundbeck Foundation [R83-A6761, R151-2013 14806]
- National Health and Medical Research Council of Australia (NHMRC) [1008307]
- Lundbeck Foundation [R192-2015-895, R83-2011-6761] Funding Source: researchfish
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 alpha-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 alpha-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 alpha-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 alpha-synuclein degradation and alpha-synuclein accumulation in neurons. MPR300 is downregulated in brain from alpha-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.
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