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

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 auto -fluorescent 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 gem-fibrozil, an activator of peroxisome proliferator-activated receptor a (PPARa) 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 acti-vation, 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 Cln3Aex7/8 (Cln3AJNCL) mice of both sexes. Accordingly, gemfibrozil treatment also improved locomotor activities of Cln3AJNCL mice. While investigating the mechanism, we found marked loss of PPARa in the SBF cortex of Cln3AJNCL mice, which increased af-ter gemfibrozil treatment. Oral gemfibrozil also stimulated the recruitment of PPARa to the Tfeb gene promoter in vivo in the SBF cortex of Cln3AJNCL mice, indicating increased transcription of Tfeb in the CNS by gemfibrozil treatment via PPARa. Moreover, disease pathologies aggravated in Cln3AJNCL mice lacking PPARa (Cln3AJNCLAPPARa) and gemfibrozil remained unable to decrease SCMAS accumulation, reduce glial activation, and improve locomotor performance of Cln3AJNCLAPPARa mice. These results suggest that activation of PPARa may be beneficial for JNCL and that gemfibrozil may be repurposed for the treatment of this incurable disease.

Automated summary

In this study, gemfibrozil was found to alleviate disease pathology, reduce neuroinflammation, restore the level of TFEB, and decrease the accumulation of SCMAS in an animal model of JNCL. Gemfibrozil treatment also improved locomotor activities. These findings suggest that PPARa activation may be beneficial for JNCL and gemfibrozil may be repurposed for its treatment.