TABLE 1.

α-synuclein post-translational modifications.

PTM	Site	Method of identification in α-synucleinopathy tissues	Putative functions
Phosphorylation	Ser129	Mass spectrometry of purified LBs (Anderson et al., 2006)/insoluble fractions from DLB brains (Fujiwara et al., 2002)	Increases α-synuclein insolubility in transgenic mouse oligodendrocytes and PD brains (Kahle et al., 2002; Zhou et al., 2011)
			Increases α-synuclein oligomerization in flies (Chen et al., 2009)
			Increases the formation of α-synuclein cytoplasmatic inclusion in SH-SY5Y cells (Smith et al., 2005)
			Increases α-synuclein neurotoxicity in SH-SY5Y cells and flies (Chau et al., 2009; Chen et al., 2009)
			Co-localizes with monoubiquitinated α-synuclein in α-synucleinopathy brains (Hasegawa et al., 2002)
			Increases nuclear accumulation of α-synuclein in H4 cells (Pinho et al., 2019)
			Modulates the binding of α-synuclein to membranes in SH-SY5Y cells and mouse neural precursor cells (Visanji et al., 2011; Kuwahara et al., 2012)
			Increased α-synuclein fibrillation in vitro (Fujiwara et al., 2002)
			Increased binding affinity to metal-ions (Lu et al., 2011)
	Ser87	Western blot analysis of and immunohistochemistry of α-synucleinopathy brains using anti-phospho-Ser87 α-synuclein antibodies (Paleologou et al., 2010)	Inhibits α-synuclein fibrillation and binding to membranes in vitro (Paleologou et al., 2010) Reduces α-synuclein aggregation and toxicity in a PD rat model (Oueslati et al., 2012)
	Tyr125	Western blot analysis of DLB brain lysates using anti-phospho-Tyr125 α-synuclein antibodies (Chen et al., 2009)	Reduces α-synuclein oligomerization and neurotoxicity in flies (Chen et al., 2009) Reduces oligomerization in vitro (Negro et al., 2002)
	Tyr39	Western blot analysis and immunohistochemistry of PD brains using anti-phospho-Tyr39 α-synuclein antibodies (Mahul-Mellier et al., 2014; Brahmachari et al., 2016)	Enhances α-synuclein aggregation in HEK293 cells (Brahmachari et al., 2016) Prevents α-synuclein degradation via the autophagy and proteasome pathways in primary cortical neurons (Mahul-Mellier et al., 2014)
Nitration	Tyr39, Tyr125, Tyr133, Tyr136	Immunohistochemistry of α-synucleinopathy brains using antibodies specific to nitrated α-synuclein residues (Giasson et al., 2000)	Increases α-synuclein aggregation in HEK293 cells (Paxinou et al., 2001) Reduces the affinity of α-synuclein to synthetic vesicles and accelerated the rate of fibril formation by unmodified α-synuclein (Hodara et al., 2004)
Truncation	C-terminal truncations Asn103 Asp115, Asp119, Asn122, Tyr133, Asp135 Glu139	Mass spectrometry of purified LBs (Anderson et al., 2006)/soluble and insoluble fractions from PD and DLB brains (Ohrfelt et al., 2011; Kellie et al., 2014; Bhattacharjee et al., 2019)	Increases α-synuclein inclusion formation and promotes neurodegeneration in α-synuclein (1-120) transgenic mice and flies (Tofaris et al., 2006; Periquet et al., 2007) Assembly of C-terminally truncated α-synuclein into disease-like filaments in vitro (Crowther et al., 1998) Induce rapid co-aggregation with full-length α-synuclein in vitro and SH-SY5Y cells (Liu et al., 2005)
	N-terminal truncations 5,39,65, 66,68,71–140	Mass spectrometry of soluble and insoluble fractions from PD brains (Kellie et al., 2014)	Deletion of first 10 or 30 amino acids change the structure of α-synuclein fibrils in vitro, reducing their stability and prompting increased cross-seeding and α-synuclein pathology in wild-type mice (Terada et al., 2018)
Glycation		Western blot analysis of thermo-enriched α-synuclein from PD and DLB brains using an antibody against advanced glycation end products (anti-CEL) (Vicente Miranda et al., 2017)	Increased α-synuclein aggregation and toxicity in yeast and H4 cells, dopaminergic LUHMES cells and α-synuclein transgenic mice (Vicente Miranda et al., 2017) Promotes in vitro oligomerization and impairs binding to lipid vesicles (Vicente Miranda et al., 2017) Increases α-synuclein aggregation in vitro and lead to toxicity when applied to SH-SY5Y cells (Chen et al., 2010)
Acetylation	N-terminal	Mass spectrometry of purified LBs (Anderson et al., 2006)/soluble and insoluble fractions from PD and DLB brains (Ohrfelt et al., 2011; Kellie et al., 2014; Bhattacharjee et al., 2019)	Prevents α-synuclein aggregation and toxicity in primary neurons and mice (de Oliveira et al., 2017)
Ubiquitination	Lys12 Lys21 Lys23	Mass spectrometry of purified LBs from DLB brains (Anderson et al., 2006)	Mono- and polyubiquitination promotes α-synuclein proteasomal degradation (Shin et al., 2005; Rott et al., 2011) Ubiquitination with K63-linked chains leads to α-synuclein (endo)lysosomal degradation (Shin et al., 2005; Tofaris et al., 2011) Accumulation of ubiquitinated α-synuclein results in increased aggregation and toxicity (Rott et al., 2008, 2011)
SUMOylation		Western blot analysis of immunoprecipitated α-synuclein from PD brain lysates (Rott et al., 2011)	SUMOylation by SUMO1 increases α-synuclein aggregation in SH-SY5Y (Rott et al., 2017) and COS-7 cells (Oh et al., 2011) Preventing SUMOylation increases α-synuclein aggregation and toxicity in HEK293 cells and a PD rat model (Krumova et al., 2011) Artificially SUMOylated α-synuclein decreases fibrillation in vitro (Krumova et al., 2011; Abeywardana and Pratt, 2015) (See more details in Table 2)