Mannose 6-Phosphate Receptor Is Reduced in -Synuclein Overexpressing Models of Parkinsons Disease

Carmela Matrone, Nicolas Dzamko, Peder Madsen, Mette Nyegaard, Regina Pohlmann, Rikke Vicki Søndergaard, Louise B. Lassen, Thomas Lars Andresen, Glenda M. Halliday, Poul Henning Jensen, Morten S. Nielsen

    Research output: Contribution to journalJournal articleResearchpeer-review

    268 Downloads (Pure)

    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.
    Original languageEnglish
    Article numbere0160501
    JournalP L o S One
    Volume11
    Issue number8
    ISSN1932-6203
    DOIs
    Publication statusPublished - 2016

    Cite this

    Matrone, C., Dzamko, N., Madsen, P., Nyegaard, M., Pohlmann, R., Søndergaard, R. V., ... Nielsen, M. S. (2016). Mannose 6-Phosphate Receptor Is Reduced in -Synuclein Overexpressing Models of Parkinsons Disease. P L o S One, 11(8), [e0160501]. https://doi.org/10.1371/journal.pone.0160501
    Matrone, Carmela ; Dzamko, Nicolas ; Madsen, Peder ; Nyegaard, Mette ; Pohlmann, Regina ; Søndergaard, Rikke Vicki ; Lassen, Louise B. ; Andresen, Thomas Lars ; Halliday, Glenda M. ; Jensen, Poul Henning ; Nielsen, Morten S. / Mannose 6-Phosphate Receptor Is Reduced in -Synuclein Overexpressing Models of Parkinsons Disease. In: P L o S One. 2016 ; Vol. 11, No. 8.
    @article{909461e1fae946bd9b26bee8d9049e2f,
    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.",
    author = "Carmela Matrone and Nicolas Dzamko and Peder Madsen and Mette Nyegaard and Regina Pohlmann and S{\o}ndergaard, {Rikke Vicki} and Lassen, {Louise B.} and Andresen, {Thomas Lars} and Halliday, {Glenda M.} and Jensen, {Poul Henning} and Nielsen, {Morten S.}",
    year = "2016",
    doi = "10.1371/journal.pone.0160501",
    language = "English",
    volume = "11",
    journal = "P L o S One",
    issn = "1932-6203",
    publisher = "Public Library of Science",
    number = "8",

    }

    Matrone, C, Dzamko, N, Madsen, P, Nyegaard, M, Pohlmann, R, Søndergaard, RV, Lassen, LB, Andresen, TL, Halliday, GM, Jensen, PH & Nielsen, MS 2016, 'Mannose 6-Phosphate Receptor Is Reduced in -Synuclein Overexpressing Models of Parkinsons Disease', P L o S One, vol. 11, no. 8, e0160501. https://doi.org/10.1371/journal.pone.0160501

    Mannose 6-Phosphate Receptor Is Reduced in -Synuclein Overexpressing Models of Parkinsons Disease. / Matrone, Carmela; Dzamko, Nicolas; Madsen, Peder; Nyegaard, Mette; Pohlmann, Regina; Søndergaard, Rikke Vicki; Lassen, Louise B.; Andresen, Thomas Lars; Halliday, Glenda M.; Jensen, Poul Henning; Nielsen, Morten S.

    In: P L o S One, Vol. 11, No. 8, e0160501, 2016.

    Research output: Contribution to journalJournal articleResearchpeer-review

    TY - JOUR

    T1 - Mannose 6-Phosphate Receptor Is Reduced in -Synuclein Overexpressing Models of Parkinsons Disease

    AU - Matrone, Carmela

    AU - Dzamko, Nicolas

    AU - Madsen, Peder

    AU - Nyegaard, Mette

    AU - Pohlmann, Regina

    AU - Søndergaard, Rikke Vicki

    AU - Lassen, Louise B.

    AU - Andresen, Thomas Lars

    AU - Halliday, Glenda M.

    AU - Jensen, Poul Henning

    AU - Nielsen, Morten S.

    PY - 2016

    Y1 - 2016

    N2 - 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.

    AB - 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.

    U2 - 10.1371/journal.pone.0160501

    DO - 10.1371/journal.pone.0160501

    M3 - Journal article

    VL - 11

    JO - P L o S One

    JF - P L o S One

    SN - 1932-6203

    IS - 8

    M1 - e0160501

    ER -

    Matrone C, Dzamko N, Madsen P, Nyegaard M, Pohlmann R, Søndergaard RV et al. Mannose 6-Phosphate Receptor Is Reduced in -Synuclein Overexpressing Models of Parkinsons Disease. P L o S One. 2016;11(8). e0160501. https://doi.org/10.1371/journal.pone.0160501