Multiple cellular systems have been implicated in the degradation of α-synuclein, including proteasomes, macroautophagy, and chaperone-mediated autophagy. The results of this study also implicate the endosomal-lysosomal pathway, and the authors speculate that this pathway may specifically catalyze the degradation of a membrane-associated pool of α-synuclein, whereas autophagy degrades the aggregated forms.

Importantly, the authors identify Nedd4 as the E3 ligase involved in α-synuclein degradation via the endosomal pathway. Although a growing number of E3 ubiquitin ligases and their targets have been identified, much less is known about the mechanisms that regulate their activity. For example, recent work by Stenmark and colleagues showed that Nedd4 expression also controls the stability of beclin 1 (Platta et al., 2011), which plays a central role in endocytic trafficking. Previous work also showed that PTEN, a negative regulator of the PI3K pathway, is a key downstream target of Nedd4 (e.g.,   Read more

Multiple cellular systems have been implicated in the degradation of α-synuclein, including proteasomes, macroautophagy, and chaperone-mediated autophagy. The results of this study also implicate the endosomal-lysosomal pathway, and the authors speculate that this pathway may specifically catalyze the degradation of a membrane-associated pool of α-synuclein, whereas autophagy degrades the aggregated forms.

Importantly, the authors identify Nedd4 as the E3 ligase involved in α-synuclein degradation via the endosomal pathway. Although a growing number of E3 ubiquitin ligases and their targets have been identified, much less is known about the mechanisms that regulate their activity. For example, recent work by Stenmark and colleagues showed that Nedd4 expression also controls the stability of beclin 1 (Platta et al., 2011), which plays a central role in endocytic trafficking. Previous work also showed that PTEN, a negative regulator of the PI3K pathway, is a key downstream target of Nedd4 (e.g., Wang et al., 2007). The downstream effectors of PI3K signaling, among other roles, act to regulate cytoskeletal dynamics, and thus have a profound impact on cell motility and remodeling of neuronal morphology. Therefore, it would be of interest to examine the regulation of Nedd4 in relation to these various substrates, including α-synuclein.

Furthermore, a role for the endosomal-lysosomal pathway in neurodegeneraiton is emerging, and the study by Goldberg and colleagues further highlights the importance of this pathway and offers specific mechanistic insights that are very valuable for further research in this area.

View all comments by Dimitri Krainc

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...  Read more

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.

View all comments by George Tofaris