TY - JOUR
T1 - Caspase 1 activity influences juvenile Batten disease (CLN3) pathogenesis
AU - Burkovetskaya, Maria
AU - Bosch, Megan E.
AU - Karpuk, Nikolay
AU - Fallet, Rachel
AU - Kielian, Tammy
N1 - Funding Information:
This work was supported by the UNMC Dean’s Pediatric Research Fund and the Batten Disease Support and Research Association (BDSRA) to T.K. The authors thank Jessica Odvody for mouse genotyping and Genentech for providing the caspase 1−/−/caspase 11+/+ mice. Tammy Kielian is a Deputy Chief Editor for the Journal of Neurochemistry.
Publisher Copyright:
© 2018 International Society for Neurochemistry
PY - 2019/3
Y1 - 2019/3
N2 - 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 Δex7/8 mouse model of JNCL, whereas neuron death occurs much later in the disease process. We previously reported that Cln3 Δex7/8 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 Δex7/8 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 Δex7/8 and caspase 1-deficient mice to create Cln3 Δex7/8 /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 Δex7/8 /Casp-1 −/− mice, with phenotypes approaching that of wild-type animals. We also report a progressive age-dependent reduction in whisker length in Cln3 Δex7/8 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 Δex7/8 and Cln3 Δex7/8 /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. (Figure presented.). This article is part of the Special Issue “Lysosomal Storage Disorders”.
AB - 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 Δex7/8 mouse model of JNCL, whereas neuron death occurs much later in the disease process. We previously reported that Cln3 Δex7/8 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 Δex7/8 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 Δex7/8 and caspase 1-deficient mice to create Cln3 Δex7/8 /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 Δex7/8 /Casp-1 −/− mice, with phenotypes approaching that of wild-type animals. We also report a progressive age-dependent reduction in whisker length in Cln3 Δex7/8 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 Δex7/8 and Cln3 Δex7/8 /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. (Figure presented.). This article is part of the Special Issue “Lysosomal Storage Disorders”.
KW - CLN3
KW - Caspase 1
KW - juvenile Batten disease
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U2 - 10.1111/jnc.14480
DO - 10.1111/jnc.14480
M3 - Article
C2 - 29873075
AN - SCOPUS:85052705135
SN - 0022-3042
VL - 148
SP - 652
EP - 668
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
IS - 5
ER -