| α-Syn
(SNCA/PARK1) |
Regulation of presynaptic function through SNARE
complex and synaptic vesicle interactions. |
Forms degradation resistant aggregates that disrupt
numerous cell biological functions. Posttranslational
modifications often promote aggregation. Self-templated spread
of α-syn pathology ensues following its cell-to-cell
transmission via LAG3-mediated uptake. USP19 mediates LAG3
exocytosis. |
Burré et
al., 2018; Hijaz
and Volpicelli-Daley, 2020; Rocha et al., 2018
|
| β-Glucocerebrosidase (GBA1) |
Lysosomal enzyme responsible for glycolipid
breakdown. |
Loss of function promotes aggregation of
α-syn due to impaired endolysosomal function.
Furthermore, accumulation of GCase1 substrates is sufficient to
induce α-syn fibrillization, though evidence of substrate
accumulation in human patients is lacking. |
Do et al.,
2019; Ryan et al.,
2019; Stojkovska
et al., 2018
|
| LRRK2
(LRRK2/PARK8) |
Multifunctional GTPase, kinase, and signaling
scaffold involved in numerous cellular functions. |
LRRK2 phosphorylates 4-EBP and the ribosomal
subunit protein S15 to increase global protein translation. It
associates with β-tubulin to mediate decreased
microtubule stability. LRRK2-mediated Rab protein
phosphorylation inactivates them, compromising vesicular
sorting. |
Berwick et al.,
2019; Harvey and
Outeiro, 2019; Madureira et al., 2020
|
| VPS35
(VPS35) |
Component of heterotrimeric retromer complex
involved in cargo sorting during vesicular transport. |
D620N mutation causes a partial loss of function
that disrupts the retromer complex’s sorting function.
These defects include impaired endolysosome maturation and
autophagy, disrupted recycling of membrane receptors, and
impaired formation of mitochondrial-derived vesicles. |
Rahman and
Morrison, 2019; Sassone et al., 2020; Williams et al., 2017
|
| Parkin
(PRKN/PARK2) |
E3 ubiquitin ligase that is activated in
conjunction with PINK1 in response to mitochondrial stress.
Leads to promiscuous ubiquitination of cytosolic and
mitochondrial substrates. |
PD-associated mutations or c-Abl–mediated
Y-phosphorylation abrogates parkin E3 ligase activity, causing
an accumulation of its substrates. Accumulation of AIMP2
activates a cell death pathway called parthanatos. Accumulation
of PARIS represses mitochondrial biogenesis and function. PINK1
phosphorylates ubiquitin and parkin to mediate parkin
activation. Parkin-mediated mitochondrial OMM protein
ubiquitination targets mitochondria for clearance via mitophagy.
PINK1/parkin signaling maintains a balance between mitochondrial
fission and fusion. PINK1/parkin phosphorylate and ubiquitinate
(respectively) the protein miro, inhibiting mitochondrial
transport. |
Bader and
Winklhofer, 2020; Ge et al., 2020; Pickrell and Youle, 2015; Quinn et al., 2020; Scarffe et al.,
2014
|
| PINK1
(PINK1/PARK6) |
Mitochondria-localized protein kinase activated by
mitochondrial stress. Co-activates with parkin to mediate
mitochondrial quality control. Has parkin-independent role in
maintaining ETC. |
Major cell biological pathways overlap with
Parkin. |
Bader and
Winklhofer, 2020; Ge et al., 2020; Pickrell and Youle, 2015; Quinn et al., 2020; Scarffe et al.,
2014
|
| DJ-1
(PARK7) |
Oxidative stress sensor through covalent
modification of C106 residue, used for activation of numerous
oxidative stress pathways. |
Loss of DJ-1 leads to pleiomorphic defects in
responses to reactive chemical species such as oxidative and
glycative stress. |
Biosa et al.,
2017; Dolgacheva et
al., 2019; van der
Vlag et al., 2020
|
