A PIKfyve modulator combined with an integrated stress response inhibitor to treat lysosomal storage diseases.

Hou, William C; Massey, Lynée A; Rhoades, Derek; Wu, Yin; Ren, Wen; Frank, Chiara; Overkleeft, Herman S; Kelly, Jeffrey W

Hou, William C; Massey, Lynée A; Rhoades, Derek; Wu, Yin; Ren, Wen; Frank, Chiara; Overkleeft, Herman S; Kelly, Jeffrey W.

Afiliación

Hou WC; Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92122.
Massey LA; Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92122.
Rhoades D; Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92122.
Wu Y; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92122.
Ren W; Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92122.
Frank C; Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92122.
Overkleeft HS; Department of Bio-organic Synthesis, Leiden Institute of Chemistry, Leiden University, Leiden 2333 CC, The Netherlands.
Kelly JW; Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92122.

Proc Natl Acad Sci U S A ; 121(34): e2320257121, 2024 Aug 20.

Article en En | MEDLINE | ID: mdl-39150784

ABSTRACT

ABSTRACT

Lysosomal degradation pathways coordinate the clearance of superfluous and damaged cellular components. Compromised lysosomal degradation is a hallmark of many degenerative diseases, including lysosomal storage diseases (LSDs), which are caused by loss-of-function mutations within both alleles of a lysosomal hydrolase, leading to lysosomal substrate accumulation. Gaucher's disease, characterized by <15% of normal glucocerebrosidase function, is the most common LSD and is a prominent risk factor for developing Parkinson's disease. Here, we show that either of two structurally distinct small molecules that modulate PIKfyve activity, identified in a high-throughput cellular lipid droplet clearance screen, can improve glucocerebrosidase function in Gaucher patient-derived fibroblasts through an MiT/TFE transcription factor that promotes lysosomal gene translation. An integrated stress response (ISR) antagonist used in combination with a PIKfyve modulator further improves cellular glucocerebrosidase activity, likely because ISR signaling appears to also be slightly activated by treatment by either small molecule at the higher doses employed. This strategy of combining a PIKfyve modulator with an ISR inhibitor improves mutant lysosomal hydrolase function in cellular models of additional LSD.

Asunto(s)

Fibroblastos; Glucosilceramidasa; Enfermedades por Almacenamiento Lisosomal; Lisosomas; Fosfatidilinositol 3-Quinasas; Humanos; Fosfatidilinositol 3-Quinasas/metabolismo; Lisosomas/metabolismo; Lisosomas/efectos de los fármacos; Glucosilceramidasa/metabolismo; Glucosilceramidasa/genética; Fibroblastos/metabolismo; Fibroblastos/efectos de los fármacos; Enfermedades por Almacenamiento Lisosomal/tratamiento farmacológico; Enfermedades por Almacenamiento Lisosomal/genética; Enfermedades por Almacenamiento Lisosomal/metabolismo; Enfermedad de Gaucher/tratamiento farmacológico; Enfermedad de Gaucher/genética; Enfermedad de Gaucher/metabolismo; Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología

Palabras clave

Gaucher's disease; PIKfyve; Parkinson's disease; integrated stress response; lysosomal storage disease

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedades por Almacenamiento Lisosomal / Fosfatidilinositol 3-Quinasas / Fibroblastos / Glucosilceramidasa / Lisosomas Límite: Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos

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