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- Title
Distinct Roles In Vivo for the Ubiquitin-Proteasome System and the Autophagy-Lysosomal Pathway in the Degradation of α-Synuclein.
- Authors
Ebrahimi-Fakhari, Darius; Cantuti-Castelvetri, Ippolita; Fan, Zhanyun; Rockenstein, Edward; Masliah, Eliezer; Hyman, Bradley T.; McLean, Pamela J.; Unni, Vivek K.
- Abstract
Increased intracellular levels ofβ-synuclein are implicated in Parkinson's disease and related disorders and may be caused by alterations in the ubiquitin-proteasome system (UPS) or the autophagy-lysosomal pathway (ALP). A critical question remains how α-synuclein is degraded by neurons in vivo.To address this, our study uses α-synuclein transgenic mice, expressinghuman α-synuclein or α-synuclein eGFP under the (h)PDGF-β promoter, in combination with in vivo pharmacologic and multiphoton imaging strategies to systematically test degradation pathways in the living mouse brain. We demonstrate that the UPS is the main degradation pathway for α-synuclein under normal conditions in vivo while with increasedβ-synuclein burden theALPis recruited. Moreover,wereport alterations of theUPS inβ-synuclein transgenic mice and age dependence to the role of the UPS in α-synuclein degradation. In addition, we provide evidence that the UPS and ALPmight be functionally connected such that impairment of one can upregulate the other. These results provide a novel link between the UPS, the ALP, and β-synuclein pathology and may have important implications for future therapeutics targeting degradation pathways.
- Subjects
UBIQUITIN; PROTEASOMES; SYNUCLEINS; PARKINSON'S disease; NEURONS; TRANSGENIC mice
- Publication
Journal of Neuroscience, 2011, Vol 31, Issue 41, p14508
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.1560-11.2011