2. Academic Validation
  3. LETC inhibits α-Syn aggregation and ameliorates motor deficiencies in the L62 mouse model of synucleinopathy

LETC inhibits α-Syn aggregation and ameliorates motor deficiencies in the L62 mouse model of synucleinopathy

  • Eur J Pharmacol. 2024 May 5:970:176505. doi: 10.1016/j.ejphar.2024.176505.
Karima Schwab 1,  Silke Frahm 2,  Mandy Magbagbeolu 2,  David Horsley 3,  Elizabeth A Goatman 3,  Valeria Melis 3,  Franz Theuring 2,  Ahtsham Ishaq 4,  John M D Storey 5,  Charles R Harrington 6,  Claude M Wischik 6,  Gernot Riedel 3
Affiliations

Affiliations

  • 1 School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK; Institute of Pharmacology, Charité - Universitätsmedizin Berlin, Hessische Str. 3-4, 10115, Berlin, Germany. Electronic address: karima.schwab@abdn.ac.uk.
  • 2 Institute of Pharmacology, Charité - Universitätsmedizin Berlin, Hessische Str. 3-4, 10115, Berlin, Germany.
  • 3 School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK.
  • 4 Department of Chemistry, University of Aberdeen, Aberdeen, UK.
  • 5 Department of Chemistry, University of Aberdeen, Aberdeen, UK; TauRx Therapeutics Ltd., 395 King Street, Aberdeen, AB24 5RP, UK.
  • 6 School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK; TauRx Therapeutics Ltd., 395 King Street, Aberdeen, AB24 5RP, UK.
PMID: 38503400 DOI: 10.1016/j.ejphar.2024.176505
Abstract

Alpha-Synuclein (α-Syn) aggregation is a pathological feature of synucleinopathies, neurodegenerative disorders that include Parkinson's disease (PD). Here, we explored the efficacy of N,N,N',N'-tetraethyl-10H-phenothiazine-3,7-diamine dihydrochloride (LETC), a protein aggregation inhibitor, on α-Syn aggregation. In both cellular models and transgenic mice, α-Syn aggregation was achieved by the overexpression of full-length human α-Syn fused with a signal sequence peptide. α-Syn accumulated in transfected DH60.21 neuroblastoma cells and α-Syn aggregation was inhibited by LETC with an EC50 of 0.066 ± 0.047 μM. Full-length human α-Syn overexpressing Line 62 (L62) mice accumulated neuronal α-Syn that was associated with a decreased motor performance in the open field and automated home cage. LETC, administered orally for 6 weeks at 10 mg/kg significantly decreased α-Syn-positive neurons in multiple brain regions and this resulted in a rescue of movement deficits in the open field in these mice. LETC however, did not improve activity deficits of L62 mice in the home cage environment. The results suggest that LETC may provide a potential disease modification therapy in synucleinopathies through the inhibition of α-Syn aggregation.

Keywords

Aggregation inhibitor; Alpha-synuclein; Mouse model; Parkinson's disease.

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