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. 2021 Jun 3;13:691881. doi: 10.3389/fnagi.2021.691881

FIGURE 4.

FIGURE 4

Cross-links between ER stress and autophagy in α-SYN-mediated pathology. Accumulated α-SYN binds to GRP78 and activates ER stress. α-SYN also induces ER stress by binding to ATF6 and inhibiting its translocation to Golgi bodies. Additionally, wild-type, mutant, or phosphorylated α-SYN activates ER stress by inhibiting ER-Golgi trafficking, which leads to the accumulation of aggregated proteins. PERK/ATF4 activation that occurred due to ER stress induces BECLIN1 and LC3 expression. Oligomeric α-SYN directly activates the IRE1α/XBP1s branch and thus induces BECLIN1 expression. The expression of BECLIN1 and LC3 triggers autophagy induction. However, wild-type and mutant α-SYN inhibit autophagosome maturation by repressing RAB1A function. They also activate mTORC1 and sequester TFEB in the cytoplasm to block autophagic flux by impairing lysosomal biogenesis and function. PERK activation-mediated MKK4/p38/LAMP2A phosphorylation may promote CMA for wild-type α-SYN degradation, whereas wild-type and mutant α-SYN directly inhibit p38 activation to block CMA, and mutant α-SYN can also inhibit CMA uptake by interacting with LAMP2A.