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Chemical chaperones targeted to the endoplasmic reticulum (ER) and lysosome prevented neurodegeneration in a C9orf72 repeat expansion drosophila amyotrophic lateral sclerosis (ALS) model

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Abstract

Background

ALS is an incurable neuromuscular degenerative disorder. A familiar form of the disease (fALS) is related to point mutations. The most common one is an expansion of a noncoding GGGGCC hexanucleotide repeat of the C9orf72 gene on chromosome 9p21. An abnormal translation of the C9orf72 gene generates dipeptide repeat proteins that aggregate in the brain. One of the classical approaches for developing treatment against protein aggregation-related diseases is to use chemical chaperones (CSs). In this work, we describe the development of novel 4-phenylbutyric acid (4-PBA) lysosome/ER-targeted derivatives. We assumed that 4-PBA targeting to specific organelles, where protein degradation takes place, might reduce the 4-PBA effective concentration.

Methods

Organic chemistry synthetic methods and solid-phase peptide synthesis (SPPS) were used for preparing the 4-PBA derivatives. The obtained compounds were evaluated in an ALS Drosophila model that expressed C9orf72 repeat expansion, causing eye degeneration. Targeting to lysosome was validated by the 19F-nuclear magnetic resonance (NMR) technique.

Results

Several synthesized compounds exhibited a significant biological effect by ameliorating the eye degeneration. They blocked the neurodegeneration of fly retina at different efficacy levels. The most active CS was compound 9, which is a peptide derivative and was targeted to ER. Another active compound targeted to lysosome was compound 4.

Conclusions

Novel CSs were more effective than 4-PBA; therefore, they might be used as a new class of drug candidates to treat ALS and other protein misfolding disorders.

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Acknowledgements

We acknowledge the Israel Ministry of Science, Technology and Space (MOST), along with the Italian Ministry of Foreign Affairs and the International Cooperation Department, the Directorate General for Country Promotion (the Unit for Scientific and Technological Cooperation) for collaboration grant number 3-13325, which was awarded to A.G. and G.C. The Germany Israel Foundation (GIF) partially supported this work (Grant no. I-1410-201.9/2017) for A.G and S. E. In addition, S. A-G wishes to thank NAAMAT for the Edelson Foundation prize (Grant number: 4) for outstanding women researchers in the field of chemistry and pharmacology and for the Navon fellowship for Ph.D. students (Grant number: 2), awarded by the Israel Ministry of Science, Technology and Space. Last, we thank Steven Manch for the English editing of the article.

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Authors and Affiliations

  1. Bar-Ilan University, 5290002, Ramat-Gan, Israel

    Salome Azoulay-Ginsburg, Michal Weitman, Michal Afri & Arie Gruzman

  2. Department of Biology and Biotechnology “Charles Darwin”, Sapienza University of Rome, 00185, Rome, Italy

    Michela Di Salvio & Gianluca Cestra

  3. Institute of Molecular Biology and Pathology, National Research Council, Sapienza University of Rome, 00185, Rome, Italy

    Michela Di Salvio & Gianluca Cestra

  4. Institute of Physical and Theoretical Chemistry, TU Braunschweig, 38106, Braunschweig, Germany

    Sara Ribeiro & Simon Ebbinghaus

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  1. Salome Azoulay-Ginsburg
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Azoulay-Ginsburg, S., Di Salvio, M., Weitman, M. et al. Chemical chaperones targeted to the endoplasmic reticulum (ER) and lysosome prevented neurodegeneration in a C9orf72 repeat expansion drosophila amyotrophic lateral sclerosis (ALS) model. Pharmacol. Rep 73, 536–550 (2021). https://doi.org/10.1007/s43440-021-00226-2

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