Loss of CREST leads to neuroinflammatory responses and ALS-like motor defects in mice

Cheng Cheng,
Kan Yang,
Xinwei Wu,
Yuefang Zhang,
Shifang Shan,
Aaron Gitler,
Anirvan Ghosh and
Zilong QiuEmail author

Translational Neurodegeneration20198:13

https://doi.org/10.1186/s40035-019-0152-1

Received: 13 November 2018
Accepted: 18 March 2019
Published: 2 April 2019

Abstract

Background

Amyotrophic lateral sclerosis (ALS) is a late onset neurodegenerative disease with fast progression. ALS has heavy genetic components in which a series of genetic mutations have been identified. In 2013, Mutations of the CREST gene (also known as SS18L1), which functions as a calcium-regulated transcriptional activator, were found in sporadic ALS patients. However, the pathogenic causality and mechanisms of ALS-associated mutations of CRESTremain to be determined.

Methods

In this study, we constructed CREST knockout and Q394X knock-in mice with CRISPR/Cas9 system. Using biochemical and imaging tools, we illustrated core pathological phenotypes in CREST mutant mice and claimed the possible pathogenic mechanisms. Furthermore, we also observed locomotion defects in CREST mutant mice with behavioural tests.

Results

We demonstrate that ALS-related CREST-Q388X mutation exhibits loss-of-function effects. Importantly, the microglial activation was prevalent in CREST haploinsufficiency mice and Q394X mice mimicking the human CREST Q388X mutation. Furthermore, we showed that both CREST haploinsufficiency and Q394X mice displayed deficits in motor coordination. Finally, we identified the critical role of CREST-BRG1 complex in repressing the expression of immune-related cytokines including Ccl2 and Cxcl10 in neurons, via histone deacetylation, providing the molecular mechanisms underlying inflammatory responses within mice lack of CREST.

Conclusion

Our findings indicate that elevated inflammatory responses in a subset of ALS may be caused by neuron-derived factors, suggesting potential therapeutic methods through inflammation pathways.