Proteasome impairment by α-synuclein
Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder worldwide and characterized by the loss of dopaminergic neurons in the patients’ midbrains. Both the presence of the protein α-synuclein in intracellular protein aggregates in surviving neurons and the genetic linking o...
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| Main Authors: | , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
September 25, 2017
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| In: |
PLOS ONE
Year: 2017, Volume: 12, Issue: 9, Pages: 1-14 |
| ISSN: | 1932-6203 |
| DOI: | 10.1371/journal.pone.0184040 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1371/journal.pone.0184040 Verlag, lizenzpflichtig, Volltext: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0184040 
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| Author Notes: | Lisa Zondler, Marcus Kostka, Patrick Garidel, Udo Heinzelmann, Bastian Hengerer, Benjamin Mayer, Jochen H. Weishaupt, Frank Gillardon, Karin M. Danzer |
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| 520 | |a Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder worldwide and characterized by the loss of dopaminergic neurons in the patients’ midbrains. Both the presence of the protein α-synuclein in intracellular protein aggregates in surviving neurons and the genetic linking of the α-synuclein encoding gene point towards a major role of α-synuclein in PD etiology. The exact pathogenic mechanisms of PD development are not entirely described to date, neither is the specific role of α-synuclein in this context. Previous studies indicate that one aspect of α-synuclein-related cellular toxicity might be direct proteasome impairment. The 20/26S proteasomal machinery is an important instrument of intracellular protein degradation. Thus, direct proteasome impairment by α-synuclein might explain or at least contribute to the formation of intracellular protein aggregates. Therefore this study investigates direct proteasomal impairment by α-synuclein both in vitro using recombinant α-synuclein and isolated proteasomes as well as in living cells. Our experiments demonstrate that the impairment of proteasome activity by α-synuclein is highly dependent upon the cellular background and origin. We show that recombinant α-synuclein oligomers and fibrils scarcely affect 20S proteasome function in vitro, neither does transient α-synuclein expression in U2OS ps 2042 (Ubi(G76V)-GFP) cells. However, stable expression of both wild-type and mutant α-synuclein in dopaminergic SH-SY5Y and PC12 cells results in a prominent impairment of the chymotrypsin-like 20S/26S proteasomal protein cleavage. Thus, our results support the idea that α-synuclein in a specific cellular environment, potentially present in dopaminergic cells, cannot be processed by the proteasome and thus contributes to a selective vulnerability of dopaminergic cells to α-synuclein pathology. | ||
| 650 | 4 | |a Atomic force microscopy | |
| 650 | 4 | |a Dopaminergics | |
| 650 | 4 | |a Neurons | |
| 650 | 4 | |a Oligomers | |
| 650 | 4 | |a Parkinson disease | |
| 650 | 4 | |a Proteasomes | |
| 650 | 4 | |a Toxicity | |
| 650 | 4 | |a Transfection | |
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| 700 | 1 | |a Garidel, Patrick |e VerfasserIn |4 aut | |
| 700 | 1 | |a Heinzelmann, Udo |e VerfasserIn |4 aut | |
| 700 | 1 | |a Hengerer, Bastian |e VerfasserIn |4 aut | |
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