The neuronal ceroid lipofuscinoses (NCLs or Batten disease) are a group of at least nine autosomal recessively inherited monogenetic storage disorders. Because there are no effective therapies available, all forms of NCL invariably prove fatal after a prolonged period of disability. Indeed, for the forms of NCL that are the result of mutations in transmembrane proteins, the therapeutic outlook remains uniformly bleak. This includes juvenile NCL (JNCL); the most prevalent form of Batten disease that is the result of mutations in the CLN3 gene. Characterizing Cln3 deficient mice is now revealing important clues about the pathogenesis of JNCL. This includes evidence for elevated levels of glutamate within the JNCL CNS and cell type selective sensitivity to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) type glutamate receptor overactivation. These findings raise the possibility that AMPA-receptor blockade may potentially be beneficial in JNCL. This possibility has now begun to be tested in Cln3 mutant mice using a single intraperitoneal injection of the non-competitive AMPA antagonist EGIS-8332 by Kovács and Pearce [Kovács, A.D., Pearce, D.A., 2008. Attenuation of AMPA receptor activity improves motor skills in a mouse model of juvenile Batten disease. Exp. Neurol. 209, 288-291.]. Although a positive effect of upon motor coordination deficits in this mouse model of JNCL is reported in this acute study, it remains unclear whether EGIS-8332 provides any lasting benefit or effects upon other aspects of their disease phenotype. Although supplying the first evidence for any form of improvement in a disease-relevant phenotype in Cln3 mutant mice, more detailed studies will be needed to determine whether these preliminary findings will translate into a successful therapy for either murine or human JNCL.
- AMPA-receptor blockade
- Batten disease
- Juvenile neuronal ceroid lipofuscinosis
- Motor coordination
- Rotarod testing