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

Karima Schwab* (Corresponding Author), Silke Frahm, Mandy Magbagbeolu, David Horsley, Elizabeth Goatman, Valeria Melis, Franz Theuring, Ahtsham Ishaq, John M. D. Storey, Charles Harrington, Claude Wischik, Gernot Riedel

*Corresponding author for this work

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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.
Original languageEnglish
Article number176505
Number of pages50
JournalEuropean Journal of Pharmacology
Volume970
Early online date18 Mar 2024
DOIs
Publication statusPublished - 5 May 2024

Data Availability Statement

Data will be made available on request.

Keywords

  • Alpha-synuclein
  • Aggregation inhibitor
  • Parkinson's disease
  • Mouse model

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