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

Research output: Contribution to journalArticle

209 Citations (Scopus)

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
Externally publishedYes

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Synucleins
Autophagy
Proteasome Endopeptidase Complex
Ubiquitin
Transgenic Mice
Parkinson Disease
Up-Regulation
Pathology

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Ebrahimi-Fakhari, D., Cantuti-Castelvetri, I., Fan, Z., Rockenstein, E., Masliah, E., Hyman, B. T., ... 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

Distinct roles in vivo for the Ubiquitin-Proteasome system and the Autophagy-Lysosomal Pathway in the Degradation of α-Synuclein. / Ebrahimi-Fakhari, Darius; Cantuti-Castelvetri, Ippolita; Fan, Zhanyun; Rockenstein, Edward; Masliah, Eliezer; Hyman, Bradley T.; McLean, Pamela J; Unni, Vivek K.

In: Journal of Neuroscience, Vol. 31, No. 41, 12.10.2011, p. 14508-14520.

Research output: Contribution to journalArticle

Ebrahimi-Fakhari, D, Cantuti-Castelvetri, I, Fan, Z, Rockenstein, E, Masliah, E, Hyman, BT, McLean, PJ & Unni, VK 2011, 'Distinct roles in vivo for the Ubiquitin-Proteasome system and the Autophagy-Lysosomal Pathway in the Degradation of α-Synuclein', Journal of Neuroscience, vol. 31, no. 41, pp. 14508-14520. https://doi.org/10.1523/JNEUROSCI.1560-11.2011
Ebrahimi-Fakhari, Darius ; Cantuti-Castelvetri, Ippolita ; Fan, Zhanyun ; Rockenstein, Edward ; Masliah, Eliezer ; Hyman, Bradley T. ; McLean, Pamela J ; Unni, Vivek K. / Distinct roles in vivo for the Ubiquitin-Proteasome system and the Autophagy-Lysosomal Pathway in the Degradation of α-Synuclein. In: Journal of Neuroscience. 2011 ; Vol. 31, No. 41. pp. 14508-14520.
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