Fig. 2: Potential cellular pathways to dispose of α-Syn aggregates.

In macroautophagy, misfolded proteins and dysfunctional organelles are wrapped into a phagophore to form an autophagosome, which fuses with a lysosome to become an autolysosome for degradation of its content. ATG5 knockdown inhibits the formation of the phagophore. Chaperones support the physiological folding process of newly synthesized or misfolded proteins and target irreparably misfolded protein for degradation. The ubiquitin proteasome system (UPS), degrades misfolded proteins for proteasomal proteolysis after labeling them with a poly-ubiquitin chain by successive action of ubiquitin activation enzymes (E1, blue), ubiquitin conjugation enzymes (E2, blue), and ubiquitin ligases (E3, blue). For chaperone-mediated autophagy (CMA), HSC70 and a chaperone complex recognize a KFERQ-pentapeptide motif of a protein and bind LAMP-2A in the lysosomal membrane to target the protein for degradation by lysosomal proteases. The unfolded protein response (UPR) is activated by accumulation of unfolded or misfolded proteins in the endoplasmic reticulum via three stress sensors (EIF2AK3, IRE1α, ATF6). In its active form, EIF2AK3 can phosphorylate the α-subunit of EIF2A. This phosphorylation is leading to decreased rates of protein synthesis, which further leads to the translation of specific mRNAs, such as ATF4. IRE1α is known to activate the transcription factor XBP1. α-Syn can be released from cells into the extracellular space either as free protein or packed in exosomes formed in multivesicular bodies. ATG5 autophagy-related gene 5, LAMP-2A lysosome-associated membrane protein type 2A, HSC70 the heat shock cognate protein of 70 kDa, EIF2AK3 eukaryotic translation initiation factor 2 alpha kinase 3, EIF2A eukaryotic translation initiation factor 2A, ATF4 activating transcription factor 4, IRE1α inositol requiring enzyme 1α, XBP1 X-box-binding protein 1, ATF6 activating transcription factor 6