Pyroptotic cell death in the R6/2 mouse model of Huntington\u2019s disease: new insight on the inflammasome

Emanuela Paldino,Giuseppe Sancesario,Vincenza D’Angelo,Francesca R Fusco

doi:10.1038/s41420-020-00293-z

Emanuela Paldino, Giuseppe Sancesario + Show 2 more

Open Access

https://doi.org/10.1038/s41420-020-00293-z

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Abstract

Mechanisms of tissue damage in Huntington’s disease involve excitotoxicity, mitochondrial damage, and neuroinflammation, including microglia activation. In the present study, we investigate the role of pyroptosis process in the striatal neurons of the R6/2 mouse model of Huntington’s disease. Transgenic mice were sacrificed at 4 and 13 weeks of age. After sacrifice, histological and immunohistochemical studies were performed. We found that NLRP3 and Caspase-1 were intensely expressed in 13-week-old R6/2 mice. Moreover, NLRP3 expression levels were higher in striatal spiny projection neurons and in parvalbumin interneurons, which are prone to degenerate in HD.

Highlights

Introduction Pyroptosis is aCaspase-1 (Casp-1) dependent programmed cell death that leads to a rapid lysis of the cell[1]
Caspase-8 and NLR family pyrin domain containing 3 (NLRP3) expression in the R6/2 mice striatum We studied the distribution of the activated apoptosis marker Caspase-8 (Fig. 1) compared to the inflammasome marker NLRP3 (Fig. 2) in the mice striatum
Our group previously described the neuroprotective effects exherted by Poly (ADP-ribose) polymerase 1 (PARP-1) inhibition in the mouse R6/2 model[21], that are postulated to be mediated by an inhibition of apoptosis[22]

Summary

Introduction

Introduction Pyroptosis is aCaspase-1 (Casp-1) dependent programmed cell death that leads to a rapid lysis of the cell[1]. Pyroptosis is a programmed cell death but is dependent on a different caspase. Several inflammasomes have been described, the interest in this topic is based on its association with various diseases which is leading to the development of therapeutics that target inflammasome activity[9]. With this in mind, the aim of our work was to investigate the relevance of pyroptosis in the neuropathology of Huntington’s disease. In this study, we carried out a research to investigate the presence of pyroptosis in the striatal cells of R6/2 Huntington’s disease mouse model by comparing it to the distribution of apoptosis

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