Comparative Studies in the A30P and A53T α-Synuclein C. elegans Strains to Investigate the Molecular Origins of Parkinson's Disease

Abstract

The aggregation of α-synuclein is a hallmark of Parkinson's disease (PD) and a variety of related neurological disorders. A number of mutations in this protein, including A30P and A53T, are associated with familial forms of the disease. Patients carrying the A30P mutation typically exhibit a similar age of onset and symptoms as sporadic PD, while those carrying the A53T mutation generally have an earlier age of onset and an accelerated progression. We report two C. elegans models of PD (PDA30P and PDA53T), which express these mutational variants in the muscle cells, and probed their behavior relative to animals expressing the wild-type protein (PDWT). PDA30P worms showed a reduced speed of movement and an increased paralysis rate, control worms, but no change in the frequency of body bends. By contrast, in PDA53T worms both speed and frequency of body bends were significantly decreased, and paralysis rate was increased. α-Synuclein was also observed to be less well localized into aggregates in PDA30P worms compared to PDA53T and PDWT worms, and amyloid-like features were evident later in the life of the animals, despite comparable levels of expression of α-synuclein. Furthermore, squalamine, a natural product currently in clinical trials for treating symptomatic aspects of PD, was found to reduce significantly the aggregation of α-synuclein and its associated toxicity in PDA53T and PDWT worms, but had less marked effects in PDA30P. In addition, using an antibody that targets the N-terminal region of α-synuclein, we observed a suppression of toxicity in PDA30P, PDA53T and PDWT worms. These results illustrate the use of these two C. elegans models in fundamental and applied PD research.

Squalamine and Its Derivatives Modulate the Aggregation of Amyloid-β and α-Synuclein and Suppress the Toxicity of Their Oligomers

“…Trodusquemine was found not to directly target either the size or hydrophobicity of the oligomers at physiological concentrations, but instead to function through a mechanism based on oligomer displacement from the cell membrane in addition to its ability to modulate the kinetics of their assembly (Perni et al, 2018;Limbocker et al, 2019Limbocker et al, , 2020b. Finally, squalamine was recently reported to prevent the aggregation of αS and its associated toxicity in new C. elegans models of familial forms of PD, where its beneficial effect was more pronounced in A53T worms than in the A30P ones (Perni et al, 2021).…”

From Marine Metabolites to the Drugs of the Future: Squalamine, Trodusquemine, Their Steroid and Triterpene Analogues

“…Similar properties were later shown for trodusquemine and αS, amyloid-beta (Aβ), and HypF-N oligomers [118,[150][151][152]. Squalamine effectively restores disordered colonic motility by restoring excitability of the enteric nervous system in a mouse model [15] and reduced toxicity of αS in a C. elegans model of Parkinson's disease [153]. In experiments modeling Alzheimer's disease in C. elegans, trodusquemine reduced the toxicity of Aβ aggregates by preventing their binding to cell membranes [154].…”

“…Neuroprotective In vitro: alpha-synuclein, amyloid-beta [148,149]; in animal models of Parkinson's disease [15,153]; phase 2 clinical trilas of squalamine phosphate for Parkinson's disease [22,158] In vitro: alpha-synuclein, amyloid-beta, HypF-N [119,[152][153][154][155]157] In animal models of Parkinson's and Alzheimer's diseases (presumably PTP1B is also involved) [157,[159][160][161]…”

Anti-α-synuclein Toxicity and Anti-neurodegenerative Role of Chrysin in Transgenic Caenorhabditis elegans Models of Parkinson’s Disease

“…elegans is a suitable model for neurodegenerative research. The worms have an easy culture method, a short life cycle with a simple neuron network, and a conserved nervous system pathway . Here, we consider chrysin, a flavonoid, as prophylactic and adjuvant agents for its advantageous effects on PD.…”