Abstract
CLN6-Batten disease is a rare neurodegenerative disorder with no cure, characterized by accumulation of lipofuscin in the lysosome, glial activation, and neuronal death. Here we test the therapeutic efficacy of modulating collapsin response mediator protein 2 (CRMP2) activity via S-N-benzy-2-acetamido-3-methoxypropionamide ((S)-Lacosamide) in a mouse model of CLN6-Batten disease. Promisingly, mouse neuronal cultures as well as Cln6 patient fibroblasts treated with varying concentrations of (S)-Lacosamide showed positive restoration of lysosomal associated deficits. However, while acute in vivo treatment enhanced glial activation in 3-month-old Cln6 mutant mice, chronic treatment over several months did not improve behavioral or long-term survival outcomes. Therefore, modulation of CRMP2 activity via (S)-Lacosamide alone is unlikely to be a viable therapeutic target for CLN6-Batten disease.
Highlights
ceroid-lipofuscinosis neuronal protein 6 (CLN6)-Batten disease is a rare, autosomal recessive, neurodegenerative disorder with no cure
While there are many subforms of Batten disease, the CLN6 variant arises from various mutations in the CLN6 gene, the most common of which leads to a frameshift mutation and ultimate loss of expression of the CLN6 protein [1]
While CLN6 has not been found to colocalize with any lysosomal markers, loss of CLN6 leads to classic Batten disease pathology, including accumulation of aggregates in the lysosome (autofluorescent storage material, mitochondrial ATP synthase subunit C (SubunitC)), enhanced glial activation, neuron loss, motor, visual, and memory/learning decline, and early death
Summary
CLN6-Batten disease is a rare, autosomal recessive, neurodegenerative disorder with no cure. While CLN6 has not been found to colocalize with any lysosomal markers, loss of CLN6 leads to classic Batten disease pathology, including accumulation of aggregates in the lysosome (autofluorescent storage material, mitochondrial ATP synthase subunit C (SubunitC)), enhanced glial activation, neuron loss, motor, visual, and memory/learning decline, and early death. One reason for this may be CLN6’s association with the cytoskeletal collapsin response mediator protein 2 (CRMP2), which plays a role in neuronal polarization, migration, and differentiation [6], and has shown to be reduced in Cln mutant mouse brains [7,8]. While there were some positive benefits of (S)-Lacosamide on Cln mouse neuronal cultures and CLN6 patient fibroblasts, in vivo treatment with (S)-Lacosamide did not have positive functional effects on behavioral or survival outcomes of Cln mutant mice
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