Therapeutic potential of lithium chloride and valproic acid against neuronopathic types of mucopolysaccharidoses through induction of the autophagy process

Lidia Gaffke; Natalia Firyn; Estera Rintz; Karolina Pierzynowska; Ewa Piotrowska; Hanna Mazur-Marzec; Grzegorz Węgrzyn

doi:10.1016/j.abb.2023.109754

Therapeutic potential of lithium chloride and valproic acid against neuronopathic types of mucopolysaccharidoses through induction of the autophagy process

Arch Biochem Biophys. 2023 Oct 1:747:109754. doi: 10.1016/j.abb.2023.109754. Epub 2023 Sep 12.

Authors

Lidia Gaffke¹, Natalia Firyn², Estera Rintz², Karolina Pierzynowska², Ewa Piotrowska², Hanna Mazur-Marzec³, Grzegorz Węgrzyn²

Affiliations

¹ Department of Molecular Biology, Faculty of Biology, University of Gdańsk, Wita Stwosza 59, 80-308, Gdańsk, Poland. Electronic address: lidia.gaffke@ug.edu.pl.
² Department of Molecular Biology, Faculty of Biology, University of Gdańsk, Wita Stwosza 59, 80-308, Gdańsk, Poland.
³ Department of Marine Biology and Biotechnology, Faculty of Oceanography and Geography, University of Gdańsk, Piłsudskiego 46, 81-378, Gdynia, Poland.

PMID: 37708928
DOI: 10.1016/j.abb.2023.109754

Abstract

Mucopolysaccharidoses (MPS) are a group of inherited disorders, caused by mutations in the genes coding for proteins involved (directly or indirectly) in glycosaminoglycan (GAG) degradation. A lack or drastically decreased residual activity of a GAG-degrading enzyme leads to the storage of these compounds, thus damaging proper functions of different cells, including neurons. The disease leads to serious psycho-motor dysfunctions and death before reaching the adulthood. Until now, induction of the autophagy process was considered as one of the therapeutic strategies for treatment of diseases caused by protein aggregation (Alzheimer's, Parkinson's, and Huntington's diseases). However, this strategy has only been recently suggested as a potential therapy for MPS. In this work, we show that the pharmacological stimulation of autophagy, by using valproic acid and lithium chloride, led to accelerated degradation of accumulated GAGs. Cytotoxicity tests indicated the safety of the use of the investigated compounds. We observed an increased number of lysosomes and enhanced degradation of heparan sulfate (one of GAGs). Induction of the autophagy process was confirmed by measuring abundance of the marker proteins, including LC3-II. Moreover, inhibition of this process resulted in abolition of the valproic acid- and LiCl-mediated reduction in GAG levels. This is the first report on the possibility of using valproic acid and lithium chloride for reducing levels of GAGs in neuronopathic forms of MPS.

Keywords: Autophagy; Glycosaminoglycan degradation; Mucopolysaccharidosis; Neuronopathic forms of mucopolysaccharidoses.