NLRP3 inflammasome as a key molecular target underlying cognitive resilience in amyotrophic lateral sclerosis

Poulomi Banerjee, Elizabeth Elliott, Olivia M Rifai, Judi O'shaughnessy, Karina McDade, Sharon Abrahams, Siddharthan Chandran, Colin Smith, Jenna Gregory

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)


Up to 50% of amyotrophic lateral sclerosis patients present with cognitive deficits in addition to motor dysfunction, butthe molecular mechanisms underlying diverse clinical and pathological presentations remain poorly understood. There istherefore an unmet need to identify molecular drivers of cognitive dysfunction to enable better therapeutic targeting andprognostication. To address this, we employed a non-biased approach to identify molecular targets using a deeplyphenotyped, clinically stratified cohort of cognitively affected and unaffected brain regions from three brain regionsof 13 amyotrophic lateral sclerosis patients with the same cognitive screening test performed during life. Using Nano-String molecular barcoding as a sensitive mRNA sequencing technique on post-mortem tissue, we profiled a data-drivenpanel of 770 genes using the Neuropathology Panel, followed by region and cell type-specific validation using BaseScopein situhybridisation and immunohistochemistry. We identified 50 significantly dysregulated genes that are distinctbetween cognitively affected and unaffected brain regions. Using BaseScopein situhybridisation, we also demonstratethat macromolecular complex regulation, notably NLRP3 inflammasome modulation, is a potential, therapeuticallytargetable, pathological correlate of cognitive resilience in ALS.
Original languageEnglish
Pages (from-to)262-268
Number of pages7
JournalThe Journal of pathology
Early online date6 Jan 2022
Publication statusPublished - Mar 2022


  • cognition
  • amyotrophic lateral sclerosis;
  • NLRP3 inflammasome
  • interleukin 6
  • nterleukin 10
  • SIRT2


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