CommentaryAlpha-synuclein and protein degradation pathways in Parkinson's disease: A pathological feed-back loop
Section snippets
Many pathways for α-synuclein degradation
The clearance of α-synuclein involves a variety of cellular intrinsic mechanisms. While α-synuclein was originally thought to be exclusively degraded by the ubiquitin-proteasome system (UPS), we now know that this protein can also be degraded inside the lysosomes, where it can be delivered by means of different pathways, like macroautophagy, chaperone-mediated autophagy and endocytosis (Cuervo et al., 2004, Ebrahimi-Fakhari et al., 2011, Mak et al., 2010, Tofaris et al., 2011, Webb et al., 2003
α-Synuclein and the UPS
The UPS is essential for the degradation of the majority of short-lived and misfolded proteins. The proteasome is a multicatalytic enzymatic complex formed by combination of a barrel-shaped catalytic core (the 20S proteasome) and different regulatory subunits (19S and 11S) that can give rise to various types of intracellular proteasomes. The best characterized type of proteasome is the 26S, which results from the assembly of the 20S catalytic core with two 19S regulatory subunits. This
α-Synuclein and the autophagy/lysosomal system
It is now well established that the UPS is not the only proteolytic system responsible for α-synuclein degradation. Indeed, lysosomes are able to eliminate all types of α-synuclein species through different pathways (Webb et al., 2003, Xilouri et al., 2013). Lysosomes are cellular organelles that contain acidic hydrolases able to break up all types of intracellular and extracellular components and macromolecules (Bohley and Seglen, 1992, Dice, 2000, Mullins and Bonifacino, 2001). When the
Macroautophagy and α-synuclein
In mammalian cells, there are various types of autophagy which differ in their mechanisms, substrate specificity, regulation and function (Cuervo, 2004) (Fig. 1). Of these, macroautophagy is the best-characterized form and is frequently referred just as “autophagy”. Macroautophagy is responsible for the degradation of most intracellular components, including entire organelles, to maintain cellular homeostasis and the appropriate balance between protein synthesis and degradation. During
Concluding remarks
As discussed above, α-synuclein can be degraded by a wide variety of proteolytic mechanisms, including the UPS and autophagy. Alterations of these degradative molecular pathways, as it occurs during normal aging, results in the abnormal accumulation α-synuclein and other substrates. On the other hand, PD-linked pathological α-synuclein (mutated, post-translationally modified or oligomeric/aggregated) can directly impair UPS and lysosomal functions and thus result in the further accumulation of
Acknowledgments
This work was supported by the European Commission Marie Curie Excellence Grant (to M.V.), Marie Curie International Reintegration Grant (to M.V.), Fundació la Caixa, Spain (to M.V.), Fondo de Investigación Sanitaria-Instituto de Salud Carlos III (FIS-ISCIII), Spain (to M.V. and M.M-V.) Ministerio de Ciencia e Innovació (MICINN), Spain (to M.V. and M.M-V.), Fundació La Marató de TV3 (to M.V.) and Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR), Spain (to M.V.).
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