Caspase 1 activity influences juvenile Batten disease (CLN3) pathogenesis

Abstract

Juvenile Neuronal Ceroid Lipofuscinosis (JNCL) is an autosomal recessive lysosomal storage disease caused by loss-of-function mutations in CLN3. Symptoms appear between 5 and 10 years of age, beginning with blindness and seizures, followed by progressive cognitive and motor decline, and premature death. Glial activation and impaired neuronal activity are early signs of pathology in the Cln3 mouse model of JNCL, whereas neuron death occurs much later in the disease process. We previously reported that Cln3 microglia are primed toward a pro-inflammatory phenotype typified by exaggerated caspase 1 inflammasome activation and here we extend those findings to demonstrate heightened caspase activity in the Cln3 mouse brain. Based on the ability of caspase 1 to cleave a large number of substrates that have been implicated in JNCL pathology, we examined the functional implications of caspase 1 inflammasome activity by crossing Cln3 and caspase 1-deficient mice to create Cln3 /Casp-1 animals. Caspase 1 deletion influenced motor behavior deficits and astrocyte activation in the context of CLN3 mutation, since both were significantly reversed in Cln3 /Casp-1 mice, with phenotypes approaching that of wild-type animals. We also report a progressive age-dependent reduction in whisker length in Cln3 mice that was partially caspase 1-dependent. However, not all CLN3 phenotypes were reversed following caspase 1 deletion, since no significant differences in lysosomal accumulation or microglial activation were observed between Cln3 and Cln3 /Casp-1 mice. Although the molecular targets of aberrant caspase 1 activity in the context of CLN3 mutation remain to be identified, our studies suggest that caspase 1 may represent a potential therapeutic target to mitigate some attributes of CLN3 disease. This article is part of the Special Issue "Lysosomal Storage Disorders".

TLR2 and caspase-1 signaling are critical for bacterial containment but not clearance during craniotomy-associated biofilm infection

“…NLRP3, ASC, and caspase-1-deficient/caspase-11-positive (Casp-1 −/− /Casp-11 +/+ ) mice were obtained from Genentech (South San Francisco, CA). Casp-1 −/− /Casp-11 +/+ animals were created by Genentech using Casp-1 −/− /Casp-11 −/− mice from The Jackson Laboratory (Bar Harbor, ME; Stock #016621; RRID: IMSR_JAX:016621) using a caspase-11 bacterial artificial chromosome to restore caspase-11 expression [19], since caspase-1 KO mice were recently shown to harbor a second mutation in caspase-11 [20]. In addition, some functions previously attributed to caspase-1 may be executed by caspase-11, such as initiation of pyroptosis, responses to infection, and noncanonical activation of caspase-1 by caspase-11 [20].…”

Lysosomal storage disorders: pathology within the lysosome and beyond

“…However, caspase‐1 inflammasome inactivation did not reverse all disease attributes in Cln3 Δex7/8 mice, since no reductions in storage material or microglial activation were observed (Burkovetskaya et al . ). This highlights the known complexity of LSDs and the need to identify fundamental processes that exert multifaceted roles in lysosomal crosstalk in order to achieve maximal therapeutic efficacy.…”

“…This Special Issue highlights some of the LSDs that impact the CNS (Bosch and Kielian ; Boudewyn and Walkley ; Burkovetskaya et al . ; Cho et al . ; Parker and Bigger ) as well as comprehensive overviews of lysosomal biology (Bajaj et al .…”

“…A functional role for the inflammasome has been demonstrated in an innovative study by Burkovetskaya et al . () in the context of juvenile Batten disease (CLN3). The impetus for this work originated from an earlier study by the same group revealing that primary microglia from the Cln3 Δex7/8 mouse model displayed aberrant caspase‐1 inflammasome activation Xiong and Kielian ().…”

“…Of note, minimal IL‐1ß protein was detected in the brains of Cln3 Δex7/8 mice, even at late stage disease (Burkovetskaya et al . ), and the lack of published evidence demonstrating inflammatory cytokine expression in the CNS during CLN3 disease suggests that aberrant caspase‐1 inflammasome activity is likely targeting proteins other than pro‐IL‐1ß to elicit neuropathological changes. This differs from other LSDs where neuroinflammation is evident, such as Gaucher disease, where recent evidence suggests a role for the NLRP3 inflammasome in regulating neuroinflammatory processes (Parker and Bigger ).…”