α-Syn and GBA1 signaling in PD.
(A) Monomeric α-syn acts as a chaperone for SNARE
proteins, promoting synaptic transmission/DA release. Certain aggregated
species of α-syn can reduce DA release by inhibiting synaptic
vesicle clustering. (B) Progressive accumulation of
α-syn aggregates is a fundamental characteristic of PD
progression. Numerous posttranslational modifications have been reported
to modulate α-syn aggregation, including pS129 (unclear effect)
via multiple kinases, pY39 (pro-aggregation) by c-Abl, and
4-hydroxy-2-nonenal (4HNE) and other modifications mediated by oxidative
stress. (C) Aggregated α-syn is incorporated into
the ER-transport machinery by USP19 and can propagate from cell to cell
via tunneling nanotubes or exosomes, or by direct LAG3-mediated uptake
into efferent neurons. (D) Endocytosed α-syn fibrils
can seed the templated aggregation of endogenous α-syn and drive
prion-like propagation. α-Syn aggregates can also be directly
imported into mitochondria, eliciting mitochondrial fragmentation and
death. The function of lysosomes, where GCase1 localizes to and
metabolizes glycolipids, is also impaired by the presence of
α-syn aggregates. (E)
GBA1-associated PD is thought to be closely linked to
dysregulation of α-syn proteostasis. Likewise, sporadic PD is
thought to drive impairments in GCase1 activity. In patients carrying
mutant GBA1 alleles, coding mutations in the GCase1
protein may lead to misfolding in the ER, leading to direct
coaggregation with α-syn or indirectly causing α-syn
aggregation by impairing autophagy. In sporadic PD, loss of GCase1
function may be driven by coaggregation with α-syn, which then
serves as a positive feedback loop to accelerate further α-syn
aggregation. In addition, accumulation of GCase1 substrates such as
GlcCer and glucosylsphingosine (GlcSph) is sufficient to trigger
α-syn aggregation.