(S)-ML-SA1 Activates Autophagy via TRPML1-TFEB Pathway

Autor(es)

Cunha, Micael R. ; Do Amaral, Bruno S. ; Takarada, Jessica E. ; Valderrama, Gabriel V. ; Batista, Andrea N. L. ; Batista Jr, Joao M. ; Cass, Quezia B. ; Counago, Rafael M. ; Massirer, Katlin B.

• Tipo de documento: Artigo Científico
• Fonte: CHEMBIOCHEM; v. 25, n. 22, p. 7-pg., 2024-08-12.

Resumo

Autophagic flux plays a crucial role in various diseases. Recently, the lysosomal ion channel TRPML1 has emerged as a promising target in lysosomal storage diseases, such as mucolipidosis. The discovery of mucolipin synthetic agonist-1 (ML-SA1) has expanded our understanding of TRPML1 ' s function and its potential therapeutic uses. However, ML-SA1 is a racemate with limited cellular potency and poor water solubility. In this study, we synthetized rac-ML-SA1, separated the enantiomers by chiral liquid chromatography and determined their absolute configuration by vibrational circular dichroism (VCD). In addition, we focused on investigating the impact of each enantiomer of ML-SA1 on the TRPML1-TFEB axis. Our findings revealed that (S)-ML-SA1 acts as an agonist for TRPML1 at the lysosomal membrane. This activation prompts transcription factor EB (TFEB) to translocate from the cytosol to the nucleus in a dose-dependent manner within live cells. Consequently, this signaling pathway enhances the expression of coordinated lysosomal expression and regulation (CLEAR) genes and activates autophagic flux. Our study presents evidence for the potential use of (S)-ML-SA1 in the development of new therapies for lysosomal storage diseases that target TRPML1. (AU)

• Processo FAPESP: 20/02006-0 - Caracterização molecular e estrutural de proteínas de ligação a RNA como alvos terapêuticos em câncer e neurologia
• Beneficiário: Katlin Brauer Massirer
• Modalidade de apoio: Auxílio à Pesquisa - Parceria para Inovação Tecnológica - PITE
• Processo FAPESP: 21/04853-4 - Estudo do potencial terapêutico de novos moduladores do canal de cálcio lisossomal hTRPML1
• Beneficiário: Micael Rodrigues Cunha
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 14/50897-0 - INCT 2014: Centro de Química Medicinal de Acesso Aberto
• Beneficiário: Katlin Brauer Massirer
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 19/22319-5 - Marcadores espectrais de dicroísmo circular vibracional: facilitando o assinalamento da configuração absoluta de produtos naturais
• Beneficiário: João Marcos Batista Junior
• Modalidade de apoio: Auxílio à Pesquisa - Regular