Abstract
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.
Highlights
Parkinson’s disease (PD) is a devastating neurodegenerative disease and the most frequent movement disorder in the modern Western society
Aside from other cellular and molecular aspects of α-syn related neuronal toxicity, both direct and indirect impairment of the ubiquitin proteasome system (UPS) by α-syn have been suggested to contribute to neurodegeneration in PD [21, 22, 30,31,32,33,34]
The first hint of UPS impairment in α-syn related neurodegeneration including PD, MSA and dementia with Lewy bodies (DLB) came from the observation that the occuring Lewy bodies (LBs) are strongly positive for ubiquitin [21]
Summary
Parkinson’s disease (PD) is a devastating neurodegenerative disease and the most frequent movement disorder in the modern Western society. PD is characterized by loss of dopamine secreting neurons of the substantia nigra pars compacta in the midbrain [1]. The knowledge about the underlying intracellular mechanisms of neuronal toxicity in PD is incomplete. The discovery that specific monogenic mutations, e.g. mutations in the SNCA gene. Affiliation with Boehringer Ingelheim Pharma GmbH & Co. KG does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials. None of the authors currently serve as editorial board members to PLOS ONE, have acted as an expert witness in relevant legal proceedings or currently sit on a committee for an organization that might benefit from the publication of this data
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