TABLE 1.
Impairments in different organelles related to α-syn.
| Organelle | Impairment | Study model | Mechanism |
| Mitochondria | Increased mitochondrial fragmentation | Overexpression of hWT α-syn in C. elegans (Kamp et al., 2010) | α-syn averts the building of fusion stalk |
| Decreased protein import | (1) Lipid bilayers with recombinant monomeric α-syn (Rostovtseva et al., 2015) (2) hWT α-syn overexpression in SN of rat (Lu et al., 2013) | α-syn blocks the TOM complex and VDAC | |
| (A) Increased ROS production (B) Decreased ATP synthesis | (1) Overexpression of p.A53T α-syn in mouse (Chinta et al., 2010) (2) Interaction between α-syn and mitochondria in rat brain (Martínez et al., 2018) (3) Monomers and oligomers of recombinant α-syn applied to primary rat co-cultures of neurons and astrocytes (Ludtmann et al., 2018) (4) Overexpression of hWT and p.A53T α-syn in human fetal dopaminergic primary neuronal cultures (Devi et al., 2008). (5) Aggregated α-syn applied to hESC cybrids (Reeve et al., 2015). (6) Skin fibroblast with SNCA locus triplication (Mak et al., 2011). (7) hiPSC-derived neuronal precursor cells with SNCA locus triplication (Flierl et al., 2014). (8) hiPSC-derived neurons with SNCA locus triplication incubated with monomeric, oligomeric, and fibrillar forms of α-syn (Emma et al., 2016). (9) Brains of postmortem PD patients (Devi et al., 2008). | (A and B) The impairment in complex I decreases the electron transport chain flow, which facilitates the production of ROS, with the subsequent dissipation of the electrochemical gradient necessary for the ATP synthase function (B) ROS generated by α-syn forms generates lipid peroxidation and oxidizes the ATP synthase β subunit | |
| Increased mtDNA damage | hWT α-syn overexpression in mouse (Bender et al., 2006, 2013) | The increase in ROS oxidizes the mtDNA | |
| Increased cell death | (1) Monomers and oligomers of recombinant α-syn applied to primary rat co-cultures of neurons and astrocytes (Ludtmann et al., 2018) (2) hiPSC-derived neuronal precursor cells with SNCA locus triplication (Flierl et al., 2014) | α-syn interacts directly with permeability transition pore components and decreases their threshold opening | |
| Nucleus | Increased stiff and length of DNA | Nanofluidic system with DNA from phage lambda and α-syn (Jiang et al., 2018). | Through binding to naked DNA. |
| Impaired DNA methylation | Transgenic mice expressing hWT α-syn under the Thy-1 promoter, rat B103 neuroblastoma cells and 293T human hepatocarcinoma cells (Desplats et al., 2011) | α-syn retains DNA methyltransferase 1 in the cytoplasm | |
| Impaired histone deacetylation | SH-SY5Y cells with hWT α-syn expression (Kontopoulos et al., 2006) | α-syn restricts and maintains histone deacetylases in the cytoplasm | |
| Alteration in histone methylation pattern | D. melanogaster expressing hWT α-syn ubiquitously under control of a daG32-GAL4 driver and dopaminergic differentiated SH-SY5Y cells with inducible hWT α-syn expression (Sugeno et al., 2016) | α-syn selectively enhances H3K9 mono- and dimethylation by interacting with H3K9me1/2 methyltransferase | |
| Endoplasmic Reticulum (ER) | Increased ER stress and cellular death | (1) hiPSC-derived cortical neurons overexpressing α-syn due to SNCA locus 3 (Heman-Ackah et al., 2017) (2) SH-SY5Y cell expressing pS129-α-syn (Sugeno et al., 2008) (3) LUHMES cells and mice expressing p.A30P α-syn (Paiva et al., 2018) | (1) UPR activated by induction of inositol-requiring transmembrane kinase/endoribonuclease 1α/X-box binding protein 1 pathway (2) Overactivation of UPR by induction of ER stress (3) Increasing level of ER stress with COL4A2 gen up-regulated |
| Impairment in calcium homeostasis | (1) PC-12 cell line overexpressing p.A30P or p.A53T α-syn mutant (Smith et al., 2005) (2) Mouse dopaminergic cell line (CATH.a) overexpressing hWT α-syn (Yoon et al., 2018) (3) BE(2)-M17 neuroblastoma cells expressing pA53T or p.A30P (Guardia-Laguarta) (4) Transgenic mutant p.A53T α-syn mice (Belal et al., 2012) | (1) Overexpression of ER stress markers (78-kDa glucose-regulated protein, inositol-requiring enzyme 1 and phosphorylated eukaryotic initiation factor 2α) (2) Induction of ER stress by exposure to manganese (3) α-syn relocation from cytoplasm to the vicinity of mitochondrial-associated ER membranes (4) Induction of ER stress by action of homocysteine-induced ER protein | |
| Increased cell apoptosis | (1) SH-SY5Y cells expressing hWT α-syn (Betzer et al., 2018) | (1) Activation of sarco/ER Ca2+-ATPase | |
| Aberrant vesicular traffic | (1) S. cerevisiae with null expression of ELO1, ELO2 and ELO3 concomitant to the expression of hWT α-syn, A53T or E46K (Lee et al., 2011) (2) hiPSC-derived midbrain dopamine neurons overexpressing hWT α-syn (Mazzulli et al., 2016) | (1) Accumulation of ROS within ER (2) Diffuse localization of Rab1A with ER-GA fragmentation | |
| Golgi apparatus (GA) | Increased GA fragmentation | (1) Primary rat astrocytes with overexpression of WT α-syn or A30P or A53T mutants (Liu et al., 2018) (2) LUHMES cells and mice expressing p.A30P α-syn (Paiva et al., 2018) (3) COS-7 that expressed α-syn (Gosavi et al., 2002) (4) Nigral neurons from patients with PD (Fujita et al., 2006) | (1) Activation of the transcription factor CCAAT-enhancer-binding protein homologous protein (2) Indirect mechanism by increasing level of ER stress with COL4A2 gen up-regulated (3) Accumulation of α-syn and presence of its fibrillary form (4) Unknown |
| Increased cell death | S. cerevisiae, C. elegans, and Drosophila melanogaster expressing hWT α-syn (Büttner et al., 2012) | Increasing calcium level by Ca2+/Mn2+-transporting P-type ATPase activation | |
| Impairment in ER-GA transport | (1) hESC-derived astrocytes with exposure to recombinant α-syn oligomers (Rostami et al., 2017) (2) SKNSH human neuroblastoma cells with overexpressed α-syn (Winslow et al., 2010) (3) Overexpression of hWT α-syn and A53T in a yeast model (Cooper et al., 2006) (4) Rat kidney epithelial and rat PC-12 cells overexpressing hWT and mutant p.A53T α-syn (Thayanidhi et al., 2010) | (1) Oligomers accumulation in lysosome and disruption of autophagosome/lysosome (2) Accumulation of α-syn inhibits autophagosome formation in form dependent of Rab1A (3) Cytoplasmic inclusion of α-syn suppresses ER-GA transport (4) Antagonism of soluble N-ethylmaleimide-sensitive factor attachment protein receptor and inhibition of docking and fusion of vesicles covered with coat protein complex II | |
| Vesicular traffic alteration and Golgi post-translational modifications | (1) S. cerevisiae that express hWT α-syn with a vector (Willingham et al., 2003) (2) S. cerevisiae with inducible expression of hWT α-syn or A53T mutant (Soper et al., 2008). (3) SH-SY5Y neuroblastoma cells with expression of α-syn (Lee et al., 2006) (4) S. cerevisiae with expression of hWT α-syn (Soper et al., 2011) | (1) Dysregulation of gene expression (glo4, mal31 or tlg2) and alteration in GTPases homeostasis (2) Accumulation of membranous vesicles with nearness of α-syn (3) Impairment of microtubule-dependent trafficking by overexpression of α-synuclein (4) Induction of accumulation and mislocalization of Rab proteins |