Activation of PPARα Exhibits Therapeutic Efficacy in a Mouse Model of Juvenile Neuronal Ceroid Lipofuscinosis

Abstract

Juvenile neuronal ceroid lipofuscinosis (JNCL) is a fatal inherited neurodegenerative disease of children that occurs because of defective function of the lysosomal membrane glycoprotein CLN3. JNCL features glial activation and accumulation of autofluorescent storage material containing subunit c of mitochondrial ATP synthase (SCMAS), ultimately resulting into neuronal loss. Until now, no effective therapy is available for JNCL. This study underlines the possible therapeutic importance of gemfibrozil, an activator of peroxisome proliferator-activated receptor α (PPARα) and a lipid-lowering drug approved by the Food and Drug Administration in an animal model of JNCL. Oral gemfibrozil treatment reduced microglial and astroglial activation, attenuated neuroinflammation, restored the level of transcription factor EB (TFEB; the master regulator of lysosomal biogenesis), and decreased the accumulation of storage material SCMAS in somatosensory barrel field (SBF) cortex of Cln3^Δex7/8 (Cln3ΔJNCL) mice of both sexes. Accordingly, gemfibrozil treatment also improved locomotor activities of Cln3ΔJNCL mice. While investigating the mechanism, we found marked loss of PPARα in the SBF cortex of Cln3ΔJNCL mice, which increased after gemfibrozil treatment. Oral gemfibrozil also stimulated the recruitment of PPARα to the Tfeb gene promoter in vivo in the SBF cortex of Cln3ΔJNCL mice, indicating increased transcription of Tfeb in the CNS by gemfibrozil treatment via PPARα. Moreover, disease pathologies aggravated in Cln3ΔJNCL mice lacking PPARα (Cln3ΔJNCL^ΔPPARα) and gemfibrozil remained unable to decrease SCMAS accumulation, reduce glial activation, and improve locomotor performance of Cln3ΔJNCL^ΔPPARα mice. These results suggest that activation of PPARα may be beneficial for JNCL and that gemfibrozil may be repurposed for the treatment of this incurable disease.SIGNIFICANCE STATEMENT Despite intense investigations, no effective therapy is available for JNCL, an incurable inherited lysosomal storage disorder. Here, we delineate that oral administration of gemfibrozil, a lipid-lowering drug, decreases glial inflammation, normalizes and/or upregulates TFEB, and reduces accumulation of autofluorescent storage material in SBF cortex to improve locomotor activities in Cln3^Δex7/8 (Cln3ΔJNCL) mice. Aggravation of disease pathology in Cln3ΔJNCL mice lacking PPARα (Cln3ΔJNCL^ΔPPARα) and inability of gemfibrozil to decrease SCMAS accumulation, reduce glial activation, and improve locomotor performance of Cln3ΔJNCL^ΔPPARα mice delineates an important role of PPARα in this process. These studies highlight a new property of gemfibrozil and indicate its possible therapeutic use in JNCL patients.

Keywords: JNCL; PPARalpha; gemfibrozil; glial activation; lysosomal storage disorder; storage materials.