Distinct roles in vivo for the Ubiquitin-Proteasome system and the Autophagy-Lysosomal Pathway in the Degradation of α-Synuclein

Darius Ebrahimi-Fakhari, Ippolita Cantuti-Castelvetri, Zhanyun Fan, Edward Rockenstein, Eliezer Masliah, Bradley T. Hyman, Pamela J. McLean, Vivek K. Unni

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Abstract

Increased intracellular levels of α-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 usesα-synuclein transgenic mice, expressinghumanα-synuclein or α-synucleineGFP under the (h)PDGF-α 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 increased α-synuclein burden theALPis recruited. Moreover,wereport alterations of theUPS in α-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 ALP might be functionally connected such that impairment of one can upregulate the other. These results provide a novel link between the UPS, the ALP, and α-synuclein pathology and may have important implications for future therapeutics targeting degradation pathways.

Original languageEnglish (US)
Pages (from-to)14508-14520
Number of pages13
JournalJournal of Neuroscience
Volume31
Issue number41
DOIs
StatePublished - Oct 12 2011

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ASJC Scopus subject areas

  • Neuroscience(all)

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Ebrahimi-Fakhari, D., Cantuti-Castelvetri, I., Fan, Z., Rockenstein, E., Masliah, E., Hyman, B. T., McLean, P. J., & Unni, V. K. (2011). Distinct roles in vivo for the Ubiquitin-Proteasome system and the Autophagy-Lysosomal Pathway in the Degradation of α-Synuclein. Journal of Neuroscience, 31(41), 14508-14520. https://doi.org/10.1523/JNEUROSCI.1560-11.2011