Tofaris GK, Kim HT, Hourez R, Jung JW, Kim KP, Goldberg AL.
Ubiquitin ligase Nedd4 promotes alpha-synuclein degradation by the endosomal-lysosomal pathway.
Proc Natl Acad Sci U S A. 2011 Oct 11;108(41):17004-9.
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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.
Platta HW, Abrahamsen H, Thoresen SB, Stenmark H.
Nedd4-dependent lysine-11-linked polyubiquitination of the tumour suppressor Beclin 1.
Biochem J. 2012 Jan 1;441(1):399-406.
Wang X, Trotman LC, Koppie T, Alimonti A, Chen Z, Gao Z, Wang J, Erdjument-Bromage H, Tempst P, Cordon-Cardo C, Pandolfi PP, Jiang X.
NEDD4-1 is a proto-oncogenic ubiquitin ligase for PTEN.
Cell. 2007 Jan 12;128(1):129-39.