Uncovering the Role of Natural and Synthetic Small Molecules in Counteracting the Burden of α-Synuclein Aggregates and Related Toxicity in Different Models of Parkinson’s Disease
Abstract
:1. Introduction
2. Natural and Synthetic Small Molecules That Affect Molecular Chaperones
Small Molecule | PD Model(s) | Target(s) | Main Proposed Effects after Small Molecule Administration | Reference |
---|---|---|---|---|
Geldanamycin | Saccharomyces cerevisiae expressing human wild-type, A30P or A53T α-Syn | SSA3 | ↓ oxidative stress ↓ apoptosis | [37] |
H4 cells co-transfected with Synphilin-1 and Syn-T | HSP70 | ↑ HSP70 ↓ α-Syn aggregation and related toxicity | [38] | |
PC12 cells overexpressing A53T α-Syn | HSP70 | ↑ HSP70 ↓ α-Syn oligomers level ↑ UPS activity | [39] | |
Drosophila flies expressing α-Syn | HSF1 HSP70 | ↑ HSP70 ↓ level of α-Syn associated toxicity | [40] | |
Intraperitoneal MPTP treatment of male C57BL/6 mice | HSP90 HSF1 HSP70 | ↓ HSP90 ↑ HSF1 ↑ HSF1:HSP70 complex ↓ dopaminergic neurotoxicity | [41] | |
17-AAG | H4 cells transfected with wild-type α-Syn | HSP90 HSP70 | ↑ HSP70 ↓ α-Syn aggregates and cytotoxicity | [43] |
19-phenyl-geldanamycin | SHSY5Y cells expressing A53T α-Syn | HSP70 HSP27 | ↑ HSP70 ↑ HSP27 ↑ cell viability ↓ higher-molecular-weight α-Syn oligomers ↑ early autophagic flux ↓ p-mTOR and p-p70S6K | [44] |
SNX-0723 | H4 cells transfected with wild-type α-Syn | HSP90 HSP70 | ↓ HSP90 ↑ HSP70 ↓ α-Syn oligomerization and cytotoxicity | [43] |
Radicicol | Yeast expressing wild-type or A53T α-Syn; Neuro2A cells expressing wild-type α-Syn | HSP90 | ↓ cell death ↓ ROS levels ↓ loss MMP ↓ nuclear DNA fragmentation | [45] |
Gedunin | MPP+ treatment N27 cells and iPSC-derived neurons | p23 | ↓ MPP+ induced neurotoxicity | [49] |
Carbenoxolone | H4 cells overexpressing wild-type α-Syn | HSF1 HSP70 | ↑ HSF1 ↑ HSP70 ↓ α-Syn aggregates and cytotoxicity | [54] |
Subcutaneous injection of rotenone in male Sprague-Dawley rats | HSF1 HSPs | ↑ HSF1 ↑ HSP70, HSP40, HSP27 ↓ α-Syn aggregation and ROS imbalance ↑ proteasome activity ↑ TH e dopamine levels ↑ motor functions | [55] | |
U-133 | Microinjection of lactacystin in male Wistar rats | HSF1 HSP70 HSP40 | ↑ HSP70 ↓ dopaminergic neurons death ↑ TH and VMAT2 ↑ α-Syn aggregates ↓ microglial activation ↑ motor functions | [56] |
Intranasal administration of lactacystin in elderly male Wistar rats | HSF1 HSP70 | ↑ HSP70 ↓ activated microgliocytes ↓ α-Syn aggregates and phosphorylation ↓ neurodegenerative process | [58] |
3. Natural and Synthetic Small Molecules That Modulate the α-Syn Aggregation Pathway and Related Toxicity
Small Molecule | PD Model(s) | Main Proposed Effects after Small Molecule Administration | Reference(s) |
---|---|---|---|
Baicalein | Differentiated PC12 cells and N2A cells expressing E46K α-Syn | ↓ cell death ↓ mitochondrial dysfunction ↓ proteasome inhibition ↓ α-Syn aggregation | [64] |
SN4741 cells expressing wild type or A53T α-Syn | ↑ cell viability ↑ macroautophagy ↓ secretion of α-Syn species | [66] | |
Intragastric rotenone administration in male C57BL/6 mice | ↓ α-Syn aggregation ↑ striatal neurotransmitters concentration ↑ behavioural functions | [67] | |
Intranigral infusion of MPP+ in male Sprague-Dawley rats | ↓ α-Syn aggregation ↓ loss of nigrostriatal dopamine content ↓ neuroinflammation ↓ MPP+-induced apoptosis and autophagy | [68] | |
EGCG | PC12 cells overexpressing wild-type α-Syn | ↓ α-Syn protein overexpression and aggregation ↓ Cu(II)-induced toxic conformation transition of α-Syn, by forming Cu(II)/EGCG complex ↓ Cu(II)-induced α-Syn protein overexpression and aggregation ↓ Cu(II)-induced cytotoxicity | [75] |
HEK-293 cells overexpressing wild-type α-Syn treated with PFF; PC12 cells treated with PFF | ↓ NP-40 fraction of α-Syn aggregates ↑ SDS-stable fraction of α-Syn aggregates ↓ α-Syn aggregates cytotoxicity | [73,76] | |
OLN-93 cells treated with α-Syn oligomers | ↓ α-Syn oligomers cytotoxicity | [78] | |
Squalamine | SH-SY5Y cells treated with α-Syn oligomers | ↓ α-Syn oligomers cytotoxicity ↓ ROS production ↓ α-Syn oligomers bound to plasma membrane | [86] |
Caenorhabditis elegans overexpressing α-Syn | ↓ α-Syn inclusions ↑ worms motility | ||
Mice overexpressing A53T human α-Syn | ↑ propagating contractile clusters velocity in vitro ↑ colonic motility in vivo ↑ ENS function | [87] | |
Trodusquemine | SH-SY5Y cells treated with α-Syn oligomers | ↓ α-Syn oligomer cytotoxicity ↓ ROS production ↓ α-Syn oligomers bound to plasma membrane | [93] |
Caenorhabditis elegans overexpressing α-Syn | ↓ α-Syn inclusions ↑ worm motility ↑ worm longevity | ||
CLR01 | HEK 293 cells expressing wild-type human α-Syn; differentiated PC12 treated with α-Syn oligomers | ↓ cell death | [96] |
Zebrafish expressing human wild-type α-Syn | ↑ embryon survival and normal phenotype ↓ α-Syn aggregates/clumps ↓ apoptosis ↑ UPS activity | ||
SH-SY5Y cells overexpressing α-Syn | ↓ α-Syn aggregates | [97] | |
iPSC-derived dopaminergic and primary rat neuronal cultures treated with LB extracts | ↓ α-Syn aggregates and cytotoxicity ↓ axonal degeneration ↓ interaction of α-Syn oligomers with axonal transport proteins | ||
Transgenic SNCA-OVX mice (12 months old) | ↓ α-Syn oligomers and astrogliosis ↑ motor function | ||
C57BL/6 wild-type mice injected with mouse PFF in the dorsal striatum or LB fractions in SN | ↓ α-Syn aggregation |
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Mohammed, S.; Russo, I.; Ramazzina, I. Uncovering the Role of Natural and Synthetic Small Molecules in Counteracting the Burden of α-Synuclein Aggregates and Related Toxicity in Different Models of Parkinson’s Disease. Int. J. Mol. Sci. 2023, 24, 13370. https://doi.org/10.3390/ijms241713370
Mohammed S, Russo I, Ramazzina I. Uncovering the Role of Natural and Synthetic Small Molecules in Counteracting the Burden of α-Synuclein Aggregates and Related Toxicity in Different Models of Parkinson’s Disease. International Journal of Molecular Sciences. 2023; 24(17):13370. https://doi.org/10.3390/ijms241713370
Chicago/Turabian StyleMohammed, Salihu, Isabella Russo, and Ileana Ramazzina. 2023. "Uncovering the Role of Natural and Synthetic Small Molecules in Counteracting the Burden of α-Synuclein Aggregates and Related Toxicity in Different Models of Parkinson’s Disease" International Journal of Molecular Sciences 24, no. 17: 13370. https://doi.org/10.3390/ijms241713370