TABLE 1.

The roles and mechanisms of PD-related factors in ER stress, autophagy and their cross-links.

PD-related factors	Roles and mechanisms in ER stress	Roles and mechanisms in autophagy	Cross-links
α-SYN	α-SYN directly binds to GRP78 to activate PERK and α-SYN reduces ATF6 processing; α-SYN oligomers activate the IRE1α-XBP1 pathway; Wild-type and mutant α-SYN affect RAB1 and disrupts traffic from the ER to the Golgi; ER stress leads to the accumulation of α-SYN oligomers.	α-SYN promotes autophagy induction by upregulating BECLIN1 and LC3 expression; α-SYN impairs autophagic flux via RAB1A inhibition, TFEB sequestration and lysosomal inhibition; α-SYN is degraded via autophagy and CMA; Oxidized α-SYN and A53T α-SYN reduce CMA-mediated proteolysis through binding to LAMP2A or inhibit p38 activation.	α-SYN-mediated BECLIN1 and LC3 expression via ER stress activation may be involved in its role in autophagy induction; The inhibition of RAB pathway by α-SYN is both involved in ER stress activation and autophagic flux impairment.
Parkin/PINK1	Parkin is upregulated by ER stress; Parkin inhibits PERK-mediated ER stress through its E3 ligase activity; Parkin also regulates ER stress via p53-XBP1 pathway; PINK1 inhibits ER stress via PERK branch.	Parkin and PINK1 control mitochondrial homeostasis by enhancing mitophagy.	PERK/ATF4/CHOP induced Parkin, p62 and NBR expression may be involved in Parkin/PINK1-mediated mitophagy.
LRRK2	LRRK2 is partly localized in ER; LRRK2 and its pathogenic mutant G2019S phosphorylate LRS, and cause ER stress; Mutant LRKK2 binds to SERCA and leads to ER Ca2+ depletion to trigger ER stress;	LRRK2 and LRKK2-G2019S induce autophagy initiation by phosphorylating LRS; LRRK2-G2019S promotes autophagy by activating ERK; LRRK2 and LRRK2-G2019S decrease autophagic degradation by regulating p62 phosphorylation, as well as inhibit autophagosome and autolysosome formation via phosphorylating a number of RAB proteins.	LRKK2 and it mutants trigger autophagy initiation by activating ERK via LRS-meditated accumulation of misfolded proteins and ER stress. LRKK2 and it mutants activate ER stress and impair autophagic flux may also through regulating RABs functions.
DJ-1	DJ-1 regulates ER stress/UPR by binding to and stabilizing ATF4 mRNA; Oxidized DJ-1 interact with arginylated GPR78; DJ-1 is upregulated under ER stress through XBP1 branch.	DJ-1 promotes ERK-dependent autophagy; Loss of DJ-1 perturbs paraquat-induced autophagic initiation by enhancing the mTOR activity; DJ-1 deficiency in microglia impairs autophagy-mediated p62 degradation and reduces microglial-mediated α-SYN phagocytosis. DJ-1 enhances CMA activity	Oxidized DJ-1 interact with arginylated GPR78 and facilitate p62-cargo complexes to phagophore; ER stress induced DJ-1 upregulation enhances the CMA or autophagic degradation.
MPTP/MPP+	MPTP/MPP+ activates IRE1α, PERK, and ATF6 branches through enhancing CDK5 and p38 activity, as well as disturbing ER Ca2+ levels.	MPTP/MPP+ treatment increases autophagy initiation but blocks autophagic flux, probably through activating AMPK and ERK activity, and reducing mTOR activity and lysosomal hydrolase activity.	MPTP/MPP+ treatment-induced ER stress and the UPR activation contribute to autophagy induction.
6-OHDA	6-OHDA activates ER stress/UPR by phosphorylating PERK and eIF2α.	6-OHDA treatment elicits autophagy activation by activating ERK and AMPK activity, as well as BECLIN1 expression; 6-OHDA promotes autophagic flux and CMA activity.	6-OHDA-activated ER stress/UPR contributes to excessive autophagy initiation and autophagic flux.
Rotenone	Rotenone triggers ER stress involving activation of all three branches of PERK, IRE1α, and ATF6.	Rotenone treatment increases autophagy induction but inhibits autophagic flux by impairing lysosomal functions; rotenone increases mitophagy.	Rotenone-mediated ER stress/UPR stimulates autophagy induction.