Proteasome impairment by ?-synuclein.

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 ?-synuclein in intracellular protein aggregates in surviving neurons and the genetic linking of the ?-synuclein encoding gene point towards a major role of ?-synuclein in PD etiology. The exact pathogenic mechanisms of PD development are not entirely described to date, neither is the specific role of ?-synuclein in this context. Previous studies indicate that one aspect of ?-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 ?-synuclein might explain or at least contribute to the formation of intracellular protein aggregates. Therefore this study investigates direct proteasomal impairment by ?-synuclein both in vitro using recombinant ?-synuclein and isolated proteasomes as well as in living cells. Our experiments demonstrate that the impairment of proteasome activity by ?-synuclein is highly dependent upon the cellular background and origin. We show that recombinant ?-synuclein oligomers and fibrils scarcely affect 20S proteasome function in vitro, neither does transient ?-synuclein expression in U2OS ps 2042 (Ubi(G76V)-GFP) cells. However, stable expression of both wild-type and mutant ?-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 ?-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 ?-synuclein pathology.

SUBMITTER: Zondler L 

PROVIDER: S-EPMC5612461 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature