TY - JOUR
T1 - Distinct roles in vivo for the Ubiquitin-Proteasome system and the Autophagy-Lysosomal Pathway in the Degradation of α-Synuclein
AU - Ebrahimi-Fakhari, Darius
AU - Cantuti-Castelvetri, Ippolita
AU - Fan, Zhanyun
AU - Rockenstein, Edward
AU - Masliah, Eliezer
AU - Hyman, Bradley T.
AU - McLean, Pamela J.
AU - Unni, Vivek K.
PY - 2011/10/12
Y1 - 2011/10/12
N2 - 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.
AB - 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.
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U2 - 10.1523/JNEUROSCI.1560-11.2011
DO - 10.1523/JNEUROSCI.1560-11.2011
M3 - Article
C2 - 21994367
AN - SCOPUS:80054026084
SN - 0270-6474
VL - 31
SP - 14508
EP - 14520
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 41
ER -