Cellular Models of Alpha-Synuclein Aggregation: What Have We Learned and Implications for Future Study
Abstract
:1. Introduction
2. Modeling Alpha-Synuclein Aggregation in Non-hiPSC Lines: What We Can Learn and Caution with Outcome Measures
3. Modeling Alpha-Synuclein Aggregation in hiPSC-Derived Neurons: Opportunities and Challenges
4. Effects of Alpha-Synuclein on Microglia
5. Modeling Alpha-Synuclein Pathology Using Astrocytes
6. Role of the Blood–Brain Barrier in Alpha-Synuclein Pathology
6.1. In Vivo Models
6.2. Human in Vitro Models
7. Oligodendrocytes and Synucleinopathy
8. HiPSC-Derived Brain Organoids as an Emerging Modeling Platform for Synucleinopathies
9. Conclusions and Future
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Conflicts of Interest
References
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Model | α-syn Modification | Outcomes of the Study | References |
---|---|---|---|
Cell lines | |||
SH-SY5Y | Overexpression | Recipient microglia suppressed autophagy caused by enhanced expression of miR-19a-3p in exosomes, via the phosphatase and tensin homolog/AKT/mTOR signaling pathway. | [26] |
Overexpression | miR-335 levels are reduced in PD models and patients. Its overexpression reduced inflammation induced by LPS stimulation or LRRK2 overexpression. | [27] | |
A53T mutation | Reduced mitochondrial oxygen flow at maximum capacity. | [28] | |
A53T mutation | Silencing of CK2α results in reduced phosphorylated α-syn at serine129 expression in cells with A53T mutation as well as functionality of dopaminergic neurons and ROS generation. | [29] | |
PFFs | Micropinocytosis was suggested to be the main pathway of α-syn internalization into SH-SY5Y cells and differentiated neurons. | [30] | |
PFFs | Higher secretion levels of nanoscopic α-syn aggregates were driven by disrupted protein homeostasis caused by PFF, but it does not lead to aggregation in the cells. | [31] | |
Monomers, dimers, tetramers | α-syn dimer and tetramer internalization into the cell happened primarily through endocytosis. Aggregated α-syn from PFFs or oligomers displayed more prominent accumulation than monomers. Tetramer structures of α-syn showed more resistance to these processes, which suggested higher infectiousness of higher oligomeric states. | [32] | |
Monomers, polymers,α-syn-119 | 1:4 ratio of α-syn -119:PQQ (pyrroloquinoline quinone) resulted in neuroprotective effect, showing antioxidant effect of PQQ. PQQ can change the secondary structure of α-syn, inhibiting oligomer formation induced by Cu(II). | [33] | |
PC12 | Overexpression | Glutamine can enhance Hsp70 expression which is able to promote degradation of α-syn even in the presence of a proteasomal inhibitor. | [34] |
Overexpression | Increase in oligomerization and aggregation of α-syn might be the result of iron accumulation in neurons. The abnormal iron levels can be caused by higher levels of α-syn concentration in the cells. | [35] | |
Oligomers and overexpression | Serotonin aldehyde oligomerizes α-syn in vivo and in vitro. | [36] | |
A53T mutation | Ubiquitin proteasome system dysfunctions caused by α-syn in dopaminergic neurons | [37] | |
PFFs | PC12 cell line is less resistant to α-syn cytotoxicity than primary hippocampal neurons. | [38] | |
PFFs | α-syn fibril formation can be inhibited by hydroxytyrosol, and fibrils can be destabilized by hydrotyrosol. | [39] | |
(MPP+)-treated cells | Low-intensity ultrasounds stimulation results in ROS generation inhibition in MPP+ treated cells, lowering levels of α-syn aggregation. | [40] | |
LUHMES | Overexpression | Transcriptome and proteasome analyses identified differential regulation of genes associated with PD. Vesicular transport and the lysosome were leading mechanisms. | [41] |
SNCA knockout | 401 genes associated to the cell cycle had reduced expression after SNCA knockout in dopaminergic neurons. | [42] | |
Overexpression | During drug screening, PDE1A inhibition showed the most effective results against α-syn toxicity. | [43] | |
A30P mutation | Overexpression of WT and A30P m α-syn had a significant effect in DNA methylation of genes related to glutamate signaling and locomotor pathways | [44] | |
MN9D | Normal expression | α-syn accumulation was inhibited by suppression of prolonged adenosine A1 receptor activation. | [45] |
Normal expression | Damage induced by 6-OHDA can be reduced by icaritin (ICT). ICT increases SOD activity, TH expression, but decreased ROS production and α-syn expression. | [46] | |
BV2 | A53T mutation | Polygala saponins fractions inhibited NLRP3 inflammasome by AMPK/mTOR and PINK1/parkin pathways, which contribute to the regulation of neuroinflammation decrease and neuronal death via mitophagy | [47] |
α-syn and MPP+ co-treatment | α-syn and MPP+ co-treatment induced activation of NLRP3 inflammasome. | [48] | |
Monomers, oligomers | Monomeric α-syn promotes microglial inflammatory phenotype by ERK, NF-κB, and PPARγ pathways. | [49] | |
α-syn -enriched conditioned media | Neuroinflammation caused by impairment in microglial autophagy is disrupted by α-syn on the Tlr4-dependent p38 and Akt-mTOR pathway. | [50] | |
PFFs | α-syn fibrils caused a strong inflammatory response. Level of fibrilization is a main trait for its intake. | [51] | |
A53T mutation | Norepinephrine release caused dopaminergic neuron viability disruption in the noradrenergic system. | [52] | |
Primary neurons | A53T α-syn T22N Rab7A mutations | Wild type Ras-related in brain 7 (Rab7) reduced α-syn decreased α-syn toxicity, e.g., oxidative stress, mitochondrial perturbations, and DNA damage. | [53] |
PFFs and α-syn E35K E46K E61K mutants | Lysophosphatidylcholine acyltransferase 1 regulates α-syn pathology. Utilization of α-syn E35K E46K E61K model. | [54] | |
LRRK2 inhibition | α-syn localization at the presynaptic terminal is connected to the kinase activity of LRRK2. | [55] | |
PFFs | α-syn aggregation induced by PFFs is not influenced by insulin-related signaling in primary dopamine neurons. | [56] | |
PFFs | Tannic acid showed the best results in two-step screening for α-syn aggregation inhibitors. | [57] | |
PFFs and AS69 protein | There is no change in PFF uptake in the presence to AS69 protein, that binds to α-syn, but AS69 decreases α-syn pathology. | [58] | |
Monomer | GLP-1R-associated neuroprotective and neurotrophic cell signaling can be activated by GLP-1 (9–36). | [59] | |
Human neural stem cell line (ReNcell) | PFF or overexpression | α-syn and its aggregate degradation can happen with miR-7 use. miR-7 can also decrease α-syn expression. | [60] |
iPSCs Model | α-syn Modification | Outcomes of the Study | References |
---|---|---|---|
iPSC- derived neurons | Overexpression | α-syn binds directly to the bTubIII and it is linked to the neuritic integrity in PD. | [111] |
A53T mutation | Higher levels (mRNA) of α-syn, early changes in expression of genes related to metabolism, differentiation/development, ion transport, cytoskeleton, extracellular matrix organization, and synaptogenesis. | [112] | |
A53T mutation | Abnormal accumulation of α-syn disrupts mRNA stability in PD iPSC neurons, disturbs the decapping module in PD brain. | [113] | |
A53T mutation and isogenic line | Increase in SNCA/α-syn can be enhanced by recombinant pro-cathepsin D. | [114] | |
A53T mutation | Neuron degradation, protein aggregates, increase in protein synthesis. | [28] | |
SNCA A53T and GBA1 mutation | ER fragmentation can be caused by the α-syn accumulation in midbrain neurons. | [115] | |
LRRK2 mutation | Carbosilane dendrimers use can counteract abnormal α-syn accumulation. | [116] | |
A53T mutation and PFFs | Generation of reliable humanized seeding model for pharmacological research. | [117] | |
PFFs and ribbons | Spreading of α-syn fibrils and ribbons, aggregation of endogenous α-syn. | [118] | |
PFFs | α-syn aggregation in the form of phosphorylated α-syn. | ||
iPSC-derived astrocytes | LRRK2 mutation | LRRK2 and GBA mutations in astrocytes contribute to PD development, manifesting several disease hallmarks. | [119] |
ATP13A2 mutation | ATP13A2 mutation in astrocytes results in α-syn accumulation in dopaminergic neurons and ATP13A2 deficiency compromises protective astrocytes function from α-syn aggregation. | [120] | |
LRRK2 mutation | Astrocytes play role in dopaminergic cell death in PD pathogenesis, by dysfunctions in pathway of protein degradation. | [121] | |
PFFs | Astrocytes and microglia revealed synchronous activity in processing α-syn aggregates. | [122] | |
PFFs | Exposure of α-syn to PFFs leads to antigen presenting phenotype in astrocytes with upregulation of major histocompatibility complex and antigen molecules, while TNF-α activates pro-inflammatory pathway. | [123] | |
PFFs | Astrocytic α-syn uptake can be limited by binding to clusterin. A-syn clearance can be improved with lower clusterin levels. | [124] | |
iPSCs-derived endothelial cells | PFFs | Generation of a substantia nigra brain chip, reproducing α-syn pathology in vivo during PFFs exposure. | [125] |
iPSCs-derived oligodendrocytes and midbrain spheroids | Overexpression and A53T mutation | PD and MSA can affect oligodendrocytes in early cellular pathways and alterations. Epigenetic, genetic changes, and immune reactivity in MSA can be connected to each other by immune component triggered by α-syn. | [126] |
Organoids (iPSCs) | Overexpression | SNCA triplication in midbrain organoids revealed pathological hallmarks of synucleinopathies in glial and neuronal cells. | [127] |
PINK1 mutation | 2-Hydroxypropyl-β-Cyclodextrin treatment resulted in mitophagy improvement and better dopaminergic differentiation by protein levels modifications. | [128] | |
PARKIN mutation | Mutation in PARKIN results in reduced IF activity. | [129] | |
PINK1 mutation | Decreased amount of dopamine in vesicles, higher expression of α-syn. | [130] | |
LRRK2 mutation | Midbrain organoids with LRRK2 mutation showed 3D pathological hallmarks of sporadic PD in patients. Thiol oxidoreductase functions are important in the LRRK2-associated PD development. | [131] | |
APOE knockout | Lower levels of apoE induce aggregation of insoluble α-syn and phosphorylated α-syn, increased synapse loss, excess lipid droplet formation (hence GBA reduction and endo-lysosomal dysregulation). | [132] | |
PFFs | Enteroendocrine cells are a key component of gut-brain hypothesis for the outcome and α-syn pathology development, and they show uptake and propagation of PFFs to neurons. | [133] | |
Organoids (ESC-derived) | GBA1 knockout and overexpression | β-sheet–rich α-syn aggregates can be the result of loss of glucocerebrosidase, linked with α-syn overexpression. | [134] |
DNAJC6 mutation | Loss of function in DNAJ6 gene results in α-syn aggregation caused by impairment in autophagy. | [135] |
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Albert, K.; Kälvälä, S.; Hakosalo, V.; Syvänen, V.; Krupa, P.; Niskanen, J.; Peltonen, S.; Sonninen, T.-M.; Lehtonen, Š. Cellular Models of Alpha-Synuclein Aggregation: What Have We Learned and Implications for Future Study. Biomedicines 2022, 10, 2649. https://doi.org/10.3390/biomedicines10102649
Albert K, Kälvälä S, Hakosalo V, Syvänen V, Krupa P, Niskanen J, Peltonen S, Sonninen T-M, Lehtonen Š. Cellular Models of Alpha-Synuclein Aggregation: What Have We Learned and Implications for Future Study. Biomedicines. 2022; 10(10):2649. https://doi.org/10.3390/biomedicines10102649
Chicago/Turabian StyleAlbert, Katrina, Sara Kälvälä, Vili Hakosalo, Valtteri Syvänen, Patryk Krupa, Jonna Niskanen, Sanni Peltonen, Tuuli-Maria Sonninen, and Šárka Lehtonen. 2022. "Cellular Models of Alpha-Synuclein Aggregation: What Have We Learned and Implications for Future Study" Biomedicines 10, no. 10: 2649. https://doi.org/10.3390/biomedicines10102649
APA StyleAlbert, K., Kälvälä, S., Hakosalo, V., Syvänen, V., Krupa, P., Niskanen, J., Peltonen, S., Sonninen, T.-M., & Lehtonen, Š. (2022). Cellular Models of Alpha-Synuclein Aggregation: What Have We Learned and Implications for Future Study. Biomedicines, 10(10), 2649. https://doi.org/10.3390/biomedicines10102649