. Author manuscript; available in PMC: 2020 May 11.

Published in final edited form as: Glia. 2019 Jul 3;67(10):1933–1957. doi: 10.1002/glia.23671

TABLE 7.

Genes implicated in MSA or PD pathogenesis in humans or animal models

Gene	Condition	Relevant ortholog	Gene name	Identified by	Ortholog score	Notes/potential mechanisms
Veil	Glia:Control	Nt5e (mouse)	5′-Nucleotidase Ecto	Schafferer et al.	14	Nt5e converts AMP to adenosine. Caffeine, an adenosine antagonist, is inversely associated with risk of development of PD (Hernán, Takkouche, Caamaño-lsorna, & Gestal-Otero, 2002; Noyce et al., 2012). Adenosine A2A receptor knockout mice are protected in animal models of PD (Kachroo & Schwarzschild, 2012; Xu et al., 2016), and adenosine antagonists are in clinical used for Parkinson’s disease in Japan (Kondo, Mizuno,, & Japanese Istradefylline Study Group, 2015). Nt5e expression is altered in PD post-mortem brains (Garcia-Esparcia, Hernandez-Ortega, Ansoleaga, Carmona, & Ferrer, 2015).
Fa2h	Glia:Control	Fa2h (mouse)	Fatty acid 2-hydroxylase	Schafferer et al.	13	Mutations in FA2H are associated with neurologic diseases including familial leukodystrophy, levodopa-responsive hereditary spastic paraplegia SPG35, and neurodegeneration with brain iron accumulation (NBIA; Kruer et al., 2010; Scheid et al., 2013; Schneider & Bhatia, 2010; Soehn et al., 2016). The Fa2h knockout mouse (K. A. Potter et al., 2011) has demyelination, axon loss, cerebellar abnormalities, and memory deficits.
CG9314	Both:Control	CAT (human)	Catalase	Langerveld et al.	12	Catalase protects cells from ROS by metabolizing H₂O₂. It is downregulated in A53T α-synuclein mice (Yakunin et al., 2014). α-synuclein induced H₂O₂ induces microglial migration toward aggregates (S. Wang et al., 2015). PD patients have reduced catalase activity in the substantia nigra (Ambani, Van Woert, & Murphy, 1975), and catalase containing nanoparticle delivery to brain has been explored as a therapeutic strategy in PD animal models (Klyachko et al., 2017).
Hsc70–1	Both:Control	HSPA8 (human)	Heat shock cognate 71 kDa protein	Langerveld et al.	11	Hsp70 is a chaperone protein that breaks down α-synuclein fibrils in vitro (Gao et al., 2015) and is upregulated in mouse models of PD (Mak, McCormack, Manning-Bog, Cuervo, & Di Monte, 2010). It may also increase extracellular release of α-synuclein (Fontaine et al., 2016).
CG5703	Both:Control	NDUFV2 (human)	NADH:Ubiquinone Oxidoreductase Core subunit V2	Langerveld et al.	11	NDUFV2 is a subunit of the mitochondrial complex 1 respiratory chain. Rare mutations have been reported as a cause of familial PD (Nishioka et al., 2010), and variants are associated with idiopathic PD in small studies (Hattori, Yoshino, Tanaka, Suzuki, & Mizuno, 1998; Mizuta et al., 2008; Swerdlow et al., 2006). The transcript was downregulated in PD patient CSF (Hossein-Nezhad et al., 2016).
Npc1b	Glia:Control	NPC1 (human)	NPC intracellular cholesterol transporter 1	Shulskaya et al.	10	Mutations in NPC1 cause the lysosomal storage disease Niemman Pick type Cl, which may predispose to α-synuclein pathology (Saito, Suzuki, Hulette, & Murayama, 2004).
CG30438	Glia:Control	Ugt8a (mouse)	UDP galactosyltransferase 8A	Schafferer et al.	10	Ugta8a knockout mice have unstable myelin, progressive demyelination and severe motor coordination deficits (Coetzee et al., 1996).
	Neuron:Control
	Both:Control
Pci	Glia:Control	CTSD (rat), CTSD (human)	Cathepsin D	Kaji et al. (Ctsd), Robak et al. (CTSD)	6^a	Mutations in CTSD cause neuronal ceroid lipofuscinosis (Myllykangas et al., 2005). CTSD cleaves α-synuclein and protects against α-synuclein aggregation and toxicity (Cullen et al., 2009; Kiely et al., 2018; Qiao et al., 2008).
Itgbetanu	Glia:Control	Itgb1 (rat)	Integrin beta-1	Kaji et al.	6	Beta 1 integrin is a subunit of many integrin receptors. It promotes microglial migration toward α-synuclein (Kim et al., 2014). It also promotes oligodendrocyte adhesion to fibronectin (Tsuboi et al., 2005), myelin formation (Camara et al., 2009), and dopaminergic neurite outgrowth (Izumi et al., 2017).
CG5278	Glia:Control	ELOVL7 (human)	Elongation of very long chain fatty acids protein 7	Sailer et al., Chang et al.	6	ELOVL7 is a fatty acid elongase. Mutations in yeast orthologs of fatty acid elongases enhance α-synuclein toxicity (Lee, Wang, Slone, Yacoubian, & Witt, 2011). Inhibiting the fatty acid desaturase SCD or its yeast ortholog OLE1 reduces levels of oleic acid and rescues α-synuclein toxicity in model organisms (Fanning et al., 2018; Vincent et al., 2018).
	Neuron:Control
	Both:Control
CG16904	Both:Control	ELOVL7 (human)	Elongation of very long chain fatty acids protein 7	Sailer et al., Chang et al.	6
CG9458	Neuron:Control	ELOVL7 (human)	Elongation of very long chain fatty acids protein 7	Sailer et al., Chang et al.	5
CG9458	Both:Control	ELOVL7 (human)	Elongation of very long chain fatty acids protein 7	Sailer et al., Chang et al.	5
CG30008	Neuron:Control	ELOVL7 (human)	Elongation of very long chain fatty acids protein 7	Sailer et al., Chang et al.	5
CG30008	Both:Control	ELOVL7 (human)	Elongation of very long chain fatty acids protein 7	Sailer et al., Chang et al.	5
CG9459	Both:Control	ELOVL7 (human)	Elongation of very long chain fatty acids protein 7	Sailer et al., Chang et al.	5
Npc2e	Glia:Control	Npc2 (mouse)	Npc intracellular cholesterol transporter 2	Schafferer et al.	5	Mutations in NPC2 cause the lyosomal storage disease Niemann Pick type C2, but heterozygotes have been reported to have a parkinsonism syndrome (Kluenemann, Nutt, Davis, & Bird, 2013).
Oatp33Ea	Glia:Control	Slco2a1 (mouse)	Solute carrier organic anion transporter family member 2A1	Schafferer et al.	4	Slco2a1 is a prostaglandin receptor expressed on microglia and endothelial cells that may play a role in neuroinflammation (Nakamura etal., 2018).
CGI5534	Glia:Control	SMPD1 (human)	Sphingomyelin phosphodiesterase 1	Robak et al.	4	SMPD1 mutations cause Niemann-Pick disease type A and B. Rare variants have been associated with PD in many small genetic studies prior to Robak et al. (reviewed in [Deng, Xiu, & Jankovic, 2015]).
Decay	Glia:Control	Casp3 (rat)	Caspase 3	Kaji et al.	4	Caspases regulate apoptosis. Inhibiting caspase 3 is protective in rat PD models (Y. Liu et al., 2013; Yuan, Ren, Wang, He, & Zhao, 2016).
Damm	Glia:Control	Casp3 (rat)	Caspase 3	Kaji et al.	4
Spn38F	Neuron:Control	Serpinbla (mouse)	Serine (or cysteine) peptidase inhibitor, clade B, member 1a	Schafferer et al.	4^a	See below for further discussion on Serpin family members.
Spn38F	Both:Control	Serpinbla (mouse)		Schafferer et al.	4^a	See below for further discussion on Serpin family members.
Cyp312al	Neuron:Control	CYP4F12 (human)	Cytochrome P450 4F12	Mills et al.	4^a	CYP4F12 is a cytochrome P450 family member that localizes to the endoplasmic reticulum and oxidizes arachidonic acid.
Cyp312al	Both:Control	CYP4F12 (human)	Cytochrome P450 4F12	Mills et al.	4^a
CG14034	Neuron:Control	Lpl (mouse)	Lipoprotein lipase	Schafferer et al.	2	Lipoprotein lipases hydrolyze long-chain triglycerides. Lpl knockout mice develop α-synuclein aggregates (Yang et al., 2015).
CG14034	Both:Control	Lpl (mouse)	Lipoprotein lipase	Schafferer et al.	2
CG18258	Neuron:Control	Lpl (mouse)	Liprotein lipase	Schafferer et al.	1^a
CG18258	Both:Control	Lpl (mouse)	Liprotein lipase	Schafferer et al.	1^a
Spn77Bb	Neuron:Control	SERPINA3 (human), SERPINA1 (human), Serpinbla (mouse)	Serpin family A member 3, Serpin family A member 1, serine (or cysteine) peptidase inhibitor, clade B, member 1a	Mills etal. (SERPINA3); Schafferer et al. (Serpinbla); Siitonen et al. (SERPINA1)	1^a	Serpin family members are protease inhibitors that participate in a wide variety of biological processes including inflammatory signaling cascades. Modified serpinA1 may be a biomarker for PD dementia (Halbgebauer et al., 2016).
Spn77Bb	Both:Control	SERPINA3 (human), SERPINA1 (human), Serpinbla (mouse)			1^a
Spn77Bc	Both:Control	SERPINA3 (human), SERPINA1 (human), Serpinbla (mouse)	Serpin family A member 3, Serpin family A member 1, serine (or cysteine) peptidase inhibitor, clade B, member 1a	Mills etal. (SERPINA3); Schafferer et al. (Serpinbla); Siitonen et al. (SERPINA1)	1^a
CG9568	Glia:Control	Cd59a (mouse)	CD59a antigen	Schafferer et al.	1^a	CD59a is a complement receptor. Complement is used by microglia to prune synapses in development (Schafer 2012) and disease (Hong et al., 2016) and causes formation of neurotoxic astrocytes (Liddelow et al., 2017).
CG9568	Both:Control	Cd59a (mouse)	CD59a antigen	Schafferer et al.	1^a
CG15635	Neuron:Control	MAGED4 (human)	MAGE family member D4	Langerveld et al.	1^a	MAGED4 enhances E3 ubiquitin ligase activity.
CG15635	Both:Control	MAGED4 (human)	MAGE family member D4	Langerveld et al.	1^a	MAGED4 enhances E3 ubiquitin ligase activity.
CG9672	Glia:Control	Prss56 (mouse)	Serine protease 56	Schafferer et al.	1^a	Prss56 is a serine protease important for eye development.
CG43897	Both:Control	PDLIM2 (human), Pdlim2 (mouse)	PDZ and LIM domain 2	Chang et al. (PDLIM2), Schafferer et al. (Pdlim2),	1^a	PDLIM2 interacts with the actin cytoskeleton and promotes anchorage-independent growth and cell migration.
Ptp52F	Glia:Control	PTPRH (human)	Protein tyrosine phosphatase, receptor type H	Jansen et al.	1^a	PTPRH is a transmembrane phosphatase. Loss of function variants enhances α-synuclein toxicity in Drosophila (Jansen et al., 2017).

Abbreviations: H₂O₂: hydrogen peroxide; ROS: reactive oxygen species.

There are multiple equally ranked orthologs for this gene. Those genes with mechanistic evidence supporting a causal role in α-synucleinopathy pathogenesis are indicated in bold.