Distinct roles In Vivo for the ubiquitin-proteasome system and the autophagy-lysosomal pathway in the degradation of α-synuclein
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 viv...
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| Main Authors: | , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
October 12, 2011
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| In: |
The journal of neuroscience
Year: 2011, Volume: 31, Issue: 41, Pages: 14508-14520 |
| ISSN: | 1529-2401 |
| DOI: | 10.1523/JNEUROSCI.1560-11.2011 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1523/JNEUROSCI.1560-11.2011 Verlag, lizenzpflichtig, Volltext: https://www.jneurosci.org/content/31/41/14508 
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| Author Notes: | Darius Ebrahimi-Fakhari, Ippolita Cantuti-Castelvetri, Zhanyun Fan, Edward Rockenstein, Eliezer Masliah, Bradley T. Hyman, Pamela J. McLean, and Vivek K. Unni |
| Summary: | 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 uses α-synuclein transgenic mice, expressing human 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 increased α-synuclein burden the ALP is recruited. Moreover, we report alterations of the UPS 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. |
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| Item Description: | Gesehen am 04.04.2022 |
| Physical Description: | Online Resource |
| ISSN: | 1529-2401 |
| DOI: | 10.1523/JNEUROSCI.1560-11.2011 |