Juvenile neuronal ceroid lipofuscinosis (JNCL) is a lysosomal storage disease caused by autosomal recessive mutations in ceroid lipofuscinosis 3 (CLN3). Children with JNCL experience progressive visual, cognitive, and motor deterioration with a decreased life expectancy (late teens-early 20s). Neuronal loss is thought to occur, in part, via glutamate excitotoxicity; however, little is known about astrocyte glutamate regulation in JNCL. Spontaneous Ca 2+ oscillations were reduced in murine Cln3 Δex7/8 astrocytes, which were also observed following glutamate or cytokine exposure. Astrocyte glutamate transport is an energy-demanding process and disruptions in metabolic pathways could influence glutamate homeostasis in Cln3 Δex7/8 astrocytes. Indeed, basal mitochondrial respiration and ATP production were significantly reduced in Cln3 Δex7/8 astrocytes. These changes were not attributable to reduced mitochondria, since mitochondrial DNA levels were similar between wild type and Cln3 Δex7/8 astrocytes. Interestingly, despite these functional deficits in Cln3 Δex7/8 astrocytes, glutamate transporter expression and glutamate uptake were not dramatically affected. Concurrent with impaired astrocyte metabolism and Ca 2+ signaling, murine Cln3 Δex7/8 neurons were hyper-responsive to glutamate, as reflected by heightened and prolonged Ca 2+ signals. These findings identify intrinsic metabolic and Ca 2+ signaling defects in Cln3 Δex7/8 astrocytes that may contribute to neuronal dysfunction in CLN3 disease. (Figure presented.). This article is part of the Special Issue “Lysosomal Storage Disorders”.
- calcium signaling
- mitochondrial dysfunction
ASJC Scopus subject areas
- Cellular and Molecular Neuroscience