Lysosomal response in relation to α-synuclein pathology differs between Parkinson's disease and multiple system atrophy
Intracellular deposition of pathologically altered α-synuclein mostly in neurons characterises Parkinson's disease (PD), while its accumulation predominantly in oligodendrocytes is a feature of multiple system atrophy (MSA). Recently a prion-like spreading of pathologic α-synuclein has been sug...
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doaj-be73ec92070f4251bb3a4b8111b2ee3b2021-03-22T12:46:21ZengElsevierNeurobiology of Disease1095-953X2018-06-01114140152Lysosomal response in relation to α-synuclein pathology differs between Parkinson's disease and multiple system atrophyGina Puska0Mirjam I. Lutz1Kinga Molnar2Günther Regelsberger3Gerda Ricken4Walter Pirker5Lajos Laszlo6Gabor G. Kovacs7Department of Anatomy, Cell and Developmental Biology, Eötvös Lorand University, Budapest, HungaryInstitute of Neurology, Medical University of Vienna, Vienna, AustriaDepartment of Anatomy, Cell and Developmental Biology, Eötvös Lorand University, Budapest, HungaryInstitute of Neurology, Medical University of Vienna, Vienna, AustriaInstitute of Neurology, Medical University of Vienna, Vienna, AustriaDepartment of Neurology, Wilhelminenspital, Vienna, AustriaDepartment of Anatomy, Cell and Developmental Biology, Eötvös Lorand University, Budapest, HungaryInstitute of Neurology, Medical University of Vienna, Vienna, Austria; Corresponding author at: Institute of Neurology, Medical University of Vienna, AKH 4J, Währinger Gürtel 18-20, A-1090 Vienna, Austria.Intracellular deposition of pathologically altered α-synuclein mostly in neurons characterises Parkinson's disease (PD), while its accumulation predominantly in oligodendrocytes is a feature of multiple system atrophy (MSA). Recently a prion-like spreading of pathologic α-synuclein has been suggested to play a role in the pathogenesis of PD and MSA. This implicates a role of protein processing systems, including lysosomes, supported also by genetic studies in PD. However, particularly for MSA, the mechanism of cell-to-cell propagation of α-synuclein is yet not fully understood. To evaluate the significance of lysosomal response, we systematically compared differently affected neuronal populations in PD, MSA, and non-diseased brains using morphometric immunohistochemistry (cathepsin D), double immunolabelling (cathepsin D/α-synuclein) laser confocal microscopy, and immunogold electron microscopy for the disease associated α-synuclein. We found that i) irrespective of the presence of neuronal inclusions, the volume density of cathepsin D immunoreactivity significantly increases in affected neurons of the pontine base in MSA brains; ii) volume density of cathepsin D immunoreactivity increases in nigral neurons in PD without inclusions and with non-ubiquitinated pre-aggregates of α-synuclein, but not in neurons with Lewy bodies; iii) cathepsin D immunoreactivity frequently colocalises with α-synuclein pre-aggregates in nigral neurons in PD; iv) ultrastructural observations confirm disease-associated α-synuclein in neuronal and astrocytic lysosomes in PD; v) lysosome-associated α-synuclein is observed in astroglia and rarely in oligodendroglia and in neurons in MSA. Our observations support a crucial role for the neuronal endosomal-lysosomal system in the processing of α-synuclein in PD. We suggest a distinct contribution of lysosomes to the pathogenesis of MSA, including the possibility of oligodendroglial and eventually neuronal uptake of exogenous α-synuclein in MSA.http://www.sciencedirect.com/science/article/pii/S0969996118300615α-SynucleinCathepsin DEndosomeLysosomeMultiple system atrophyNeurodegeneration |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Gina Puska Mirjam I. Lutz Kinga Molnar Günther Regelsberger Gerda Ricken Walter Pirker Lajos Laszlo Gabor G. Kovacs |
spellingShingle |
Gina Puska Mirjam I. Lutz Kinga Molnar Günther Regelsberger Gerda Ricken Walter Pirker Lajos Laszlo Gabor G. Kovacs Lysosomal response in relation to α-synuclein pathology differs between Parkinson's disease and multiple system atrophy Neurobiology of Disease α-Synuclein Cathepsin D Endosome Lysosome Multiple system atrophy Neurodegeneration |
author_facet |
Gina Puska Mirjam I. Lutz Kinga Molnar Günther Regelsberger Gerda Ricken Walter Pirker Lajos Laszlo Gabor G. Kovacs |
author_sort |
Gina Puska |
title |
Lysosomal response in relation to α-synuclein pathology differs between Parkinson's disease and multiple system atrophy |
title_short |
Lysosomal response in relation to α-synuclein pathology differs between Parkinson's disease and multiple system atrophy |
title_full |
Lysosomal response in relation to α-synuclein pathology differs between Parkinson's disease and multiple system atrophy |
title_fullStr |
Lysosomal response in relation to α-synuclein pathology differs between Parkinson's disease and multiple system atrophy |
title_full_unstemmed |
Lysosomal response in relation to α-synuclein pathology differs between Parkinson's disease and multiple system atrophy |
title_sort |
lysosomal response in relation to α-synuclein pathology differs between parkinson's disease and multiple system atrophy |
publisher |
Elsevier |
series |
Neurobiology of Disease |
issn |
1095-953X |
publishDate |
2018-06-01 |
description |
Intracellular deposition of pathologically altered α-synuclein mostly in neurons characterises Parkinson's disease (PD), while its accumulation predominantly in oligodendrocytes is a feature of multiple system atrophy (MSA). Recently a prion-like spreading of pathologic α-synuclein has been suggested to play a role in the pathogenesis of PD and MSA. This implicates a role of protein processing systems, including lysosomes, supported also by genetic studies in PD. However, particularly for MSA, the mechanism of cell-to-cell propagation of α-synuclein is yet not fully understood. To evaluate the significance of lysosomal response, we systematically compared differently affected neuronal populations in PD, MSA, and non-diseased brains using morphometric immunohistochemistry (cathepsin D), double immunolabelling (cathepsin D/α-synuclein) laser confocal microscopy, and immunogold electron microscopy for the disease associated α-synuclein. We found that i) irrespective of the presence of neuronal inclusions, the volume density of cathepsin D immunoreactivity significantly increases in affected neurons of the pontine base in MSA brains; ii) volume density of cathepsin D immunoreactivity increases in nigral neurons in PD without inclusions and with non-ubiquitinated pre-aggregates of α-synuclein, but not in neurons with Lewy bodies; iii) cathepsin D immunoreactivity frequently colocalises with α-synuclein pre-aggregates in nigral neurons in PD; iv) ultrastructural observations confirm disease-associated α-synuclein in neuronal and astrocytic lysosomes in PD; v) lysosome-associated α-synuclein is observed in astroglia and rarely in oligodendroglia and in neurons in MSA. Our observations support a crucial role for the neuronal endosomal-lysosomal system in the processing of α-synuclein in PD. We suggest a distinct contribution of lysosomes to the pathogenesis of MSA, including the possibility of oligodendroglial and eventually neuronal uptake of exogenous α-synuclein in MSA. |
topic |
α-Synuclein Cathepsin D Endosome Lysosome Multiple system atrophy Neurodegeneration |
url |
http://www.sciencedirect.com/science/article/pii/S0969996118300615 |
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