Ebrahimi-Fakhari D, Cantuti-Castelvetri I, Fan Z, Rockenstein E, Masliah E, Hyman BT, McLean PJ, Unni VK. Distinct roles in vivo for the ubiquitin-proteasome system and the autophagy-lysosomal pathway in the degradation of α-synuclein. J Neurosci. 2011 Oct 12;31(41):14508-20. PubMed.
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Oxford University
The mechanism by which α-synuclein is cleared in neurons is central to the pathogenesis of Parkinson’s disease and in developing targeted therapies. This is because a critical level of this protein in neurons is directly linked to neurodegeneration, as evident in cases with α-synuclein gene multiplications and promoter polymorphisms. Although a number of studies in cell lines previously showed that both proteasomes and lysosomes degrade α-synuclein, the relative contribution of these two pathways to α-synuclein breakdown in neurons in the living brain is not known.
The authors of this elegant study have combined traditional pharmacologic approaches with advanced in-vivo imaging modalities to help address this important question. They showed that when an inhibitor is added to the cortical surface, endogenous α-synuclein is degraded primarily by the ubiquitin-proteasome system (UPS), whereas macroautophagy is activated by and contributes to the clearance of overexpressed α-synuclein. It remains unclear whether this differential response is due to raised levels of soluble protein or because α-synuclein is aggregated in the transgenic overproducing model.
Interestingly, in this model, the authors show an age dependence to the relevance of the UPS in α-synuclein degradation.
Based on this study and previous observations, it seems likely that there is a primary mode of clearance for a specific fraction of α-synuclein (e.g., soluble or cytoplasmic) and secondary mechanisms in response to its accumulation or misfolding. Although the study was not designed to investigate the contribution of other lysosomal pathways (e.g., endolysosomal or chaperone-mediated autophagy), it is interesting to note that, similar to work in cell culture, the increase in endogenous α-synuclein content after proteasomal inhibition was only about 1.3-fold, suggesting that under basal conditions, only a certain pool of this protein is degraded by proteasomes.
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