Lysosomal storage diseases (LSDs) are a group of rare genetic disorders characterized by the accumulation of harmful substrates due to impaired lysosomal function. Although enzyme replacement therapy has been developed for LSDs, it is ineffective for neuropathic LSD (NLSD) because it cannot penetrate the blood-brain barrier (BBB) (Li, 2018). Consequently, BBB-permeable low-molecular-weight therapeutic agents have emerged as promising alternatives for treating NLSDs (Soldati et al., 2021).
Ceroid lipofuscinosis neuronal 3 (CLN3) disease, caused by mutations in the CLN3 gene (encoding the lysosomal transmembrane protein battenin), is the most common juvenile neurodegenerative disorder (Ostergaard, 2016). Gaucher disease (GD), caused by homozygous mutations in β-glucocerebrosidase (GBA; encoding the lysosomal enzyme GCase), has the highest incidence among LSDs and is classified into 3 subtypes based on neurological symptoms (Imbalzano et al., 2024). Heterozygous GBA mutations are found in about 5–15 % of patients with Parkinson’s disease (PD) (Smith and Schapira, 2022). Recent studies have identified oxidative stress and defective autophagy as links between NLSDs and common neurodegenerative diseases (NDs) including PD (Francelle and Mazzulli, 2022).
Previously, we reported lysosomal dysfunction, increased reactive oxygen species (ROS) generation, and mortality in CLN3 patient-derived lymphoblasts (PDLs) (Hong et al., 2016, Kang et al., 2013a). Additionally, decreased levels of superoxide dismutase (SOD), an antioxidant enzyme, have been reported in CLN3 disease (Yoon et al., 2011) and GD (Kartha et al., 2020). ROS generation is also induced by reduced lipid droplet (LD) degradation (Ding et al., 2021). LDs were identified as cytoplasmic organelles in the nineteenth century and were initially thought to serve primarily for lipid storage (Walther and Farese, 2012). The accumulation of LD is closely associated with NLSDs (Schulze and Sandhoff, 2011). CLN3 exhibits increased lipid accumulation and reduced levels of lipid-degrading lysosomal enzymes (Schmidtke et al., 2019). GD results in LD accumulation, which is exacerbated by the addition of fatty acids (Smith et al., 2023). Thus, increased ROS generation and lack of LD clearance may contribute to the progression of NLSDs (Parenti et al., 2021).
Peroxisome proliferator-activated receptor γ (PPARγ) is an attractive therapeutic target for various metabolic diseases, owing to its role in regulating ROS and lipid homeostasis. PPARγ reduces oxidative stress in the central nervous system (CNS) by upregulating SOD activity (Yu et al., 2008). It suppresses NADPH oxidase (NOX)-mediated ROS generation by reducing the levels of nuclear factor κB (NF-κB) and hypoxia-inducible factor 1α (HIF1α) (Wu et al., 2016, Yuan et al., 2011, Yang et al., 2015). PPARγ agonists induce lipolysis in high-fat diet (HFD)-fed mice (Hsiao et al., 2017), reduce locomotor deficits in GD model flies (Shola-Dare et al., 2021), and decrease proinflammatory microglial cells (Mandrekar-Colucci et al., 2012). However, FDA-approved PPARγ antagonists are not available for individuals with CLN3 disease or GD.
The only FDA-approved selective PPARγ agonists are thiazolidinediones; however, their use is prohibited in children under 18 years of age (Gao et al., 2016). Resorcinol (RSC), a polyphenolic compound found in several plants, has been approved by the FDA for the treatment of acne and seborrheic dermatitis (Sütfeld et al., 1996). Additionally, it has been reported to have antioxidant and anti-inflammatory activities (Lee et al., 2021) as well as potential PPARγ agonist effects (Viladomiu et al., 2014).
Here, we investigated RSC as a potential treatment for CLN3 disease and GD, and the role of PPARγ in the pathogenesis associated with ROS generation and LD accumulation. RSC reduces ROS generation and LD accumulation in CLN3-PDLs via PPARγ agonistic effects. PPARγ-dependent therapeutic effects of RSC were also confirmed in GD type 2 (GD2; acute neuropathic) patient-derived fibroblasts (PDFs). These findings suggest that PPARγ is a therapeutic target for CLN3 disease and GD and highlight the potential of RSC as a therapeutic agent for these diseases.