| Protein (gene) . | Native function . | Major neurodegenerative pathways . | Further reading . |
|---|---|---|---|
| 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 |
| Protein (gene) . | Native function . | Major neurodegenerative pathways . | Further reading . |
|---|---|---|---|
| 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 |