Astrocytes in juvenile neuronal ceroid lipofuscinosis (CLN3) display metabolic and calcium signaling abnormalities

Abstract

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 oscillations were reduced in murine Cln3 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 astrocytes. Indeed, basal mitochondrial respiration and ATP production were significantly reduced in Cln3 astrocytes. These changes were not attributable to reduced mitochondria, since mitochondrial DNA levels were similar between wild type and Cln3 astrocytes. Interestingly, despite these functional deficits in Cln3 astrocytes, glutamate transporter expression and glutamate uptake were not dramatically affected. Concurrent with impaired astrocyte metabolism and Ca signaling, murine Cln3 neurons were hyper-responsive to glutamate, as reflected by heightened and prolonged Ca signals. These findings identify intrinsic metabolic and Ca signaling defects in Cln3 astrocytes that may contribute to neuronal dysfunction in CLN3 disease.

Neuronal Ceroid Lipofuscinoses: Connecting Calcium Signalling through Calmodulin

“…In a previous study, it was proposed that subunit c accumulation caused altered calcium signalling in electrically excitable neurons and photoreceptor cells [ 13 ]. Recent evidence continues to build a framework around aberrant calcium signalling being linked to NCL pathology [ 14 , 15 , 16 , 17 , 18 ]. For example, it has been proposed that amlodipine, a drug which reduces intracellular calcium, could function as a therapeutic for NCL patients.…”

Lysosomal storage disorders: pathology within the lysosome and beyond

“…Many of the LSDs are associated with significant central nervous system (CNS) pathology, whereas others primarily affect peripheral organs. This Special Issue highlights some of the LSDs that impact the CNS (Bosch and Kielian ; Boudewyn and Walkley ; Burkovetskaya et al . ; Cho et al .…”

“…In this Special Issue, work by Bosch and Kielian reveals that astrocytes from a mouse model of juvenile Batten disease ( Cln3 Δex7/8 ) possess defects in mitochondrial activity, which manifest as reduced ATP production both at baseline and in response to pro‐inflammatory signals presumed to be present at late stage disease in patients with CLN3 disease (Bosch and Kielian ). Since mitochondrial respiration and adenosine triphosphate (ATP) production are Ca 2+ ‐dependent, it is possible that mitochondrial deficits in Cln3 Δex7/8 astrocytes may be influenced, in part, from reduced intracellular Ca 2+ flux, which was also observed in this study (Bosch and Kielian ). These changes in Cln3 Δex7/8 astrocytes were expected to translate into impaired glutamate regulation to account for the reported accumulation of glutamate in the CNS of patients with CLN3 disease.…”

Small Molecules that Rescue Multiple Phenotypic Aberrations in an iPSC-Derived Neuron Model of CLN3 Disease

“…In addition to the significant effect of 9e on inducing Bcl-2 expression and autophagy, the small molecule successfully rescued mitochondrial dysfunction of the CLN3-derived NPCs. Basal respiration and ATP production have been reported to be significantly reduced in Cln3 Dex7/8 mouse model astrocytes (67). Basal respiration, spare respiratory capacity and ATP function of the CLN3-derived NPCs were all significantly increased to similar or greater levels as seen in healthy IMR90-c4-derived NPC controls.…”