| First Author | Bosch ME | Year | 2019 |
| Journal | J Neurochem | Volume | 148 |
| Issue | 5 | Pages | 612-624 |
| PubMed ID | 29964296 | Mgi Jnum | J:347520 |
| Mgi Id | MGI:6281053 | Doi | 10.1111/jnc.14545 |
| Citation | Bosch ME, et al. (2019) Astrocytes in juvenile neuronal ceroid lipofuscinosis (CLN3) display metabolic and calcium signaling abnormalities. J Neurochem 148(5):612-624 |
| abstractText | 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(Deltaex7/8) 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(Deltaex7/8) astrocytes. Indeed, basal mitochondrial respiration and ATP production were significantly reduced in Cln3(Deltaex7/8) astrocytes. These changes were not attributable to reduced mitochondria, since mitochondrial DNA levels were similar between wild type and Cln3(Deltaex7/8) astrocytes. Interestingly, despite these functional deficits in Cln3(Deltaex7/8) astrocytes, glutamate transporter expression and glutamate uptake were not dramatically affected. Concurrent with impaired astrocyte metabolism and Ca(2+) signaling, murine Cln3(Deltaex7/8) 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(Deltaex7/8) astrocytes that may contribute to neuronal dysfunction in CLN3 disease. This article is part of the Special Issue "Lysosomal Storage Disorders". |
