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NLRP3 inflammasome as a key molecular target underlying cognitive resilience in amyotrophic lateral sclerosis
Author(s) -
Banerjee Poulomi,
Elliott Elizabeth,
Rifai Olivia M,
O’Shaughnessy Judi,
McDade Karina,
Abrahams Sharon,
Chandran Siddharthan,
Smith Colin,
Gregory Jenna M
Publication year - 2022
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.5846
Subject(s) - amyotrophic lateral sclerosis , neuropathology , inflammasome , pathological , neuroscience , cognition , molecular pathology , medicine , bioinformatics , biology , pathology , gene , inflammation , disease , genetics
Up to 50% of amyotrophic lateral sclerosis patients present with cognitive deficits in addition to motor dysfunction, but the molecular mechanisms underlying diverse clinical and pathological presentations remain poorly understood. There is therefore an unmet need to identify molecular drivers of cognitive dysfunction to enable better therapeutic targeting and prognostication. To address this, we employed a non‐biased approach to identify molecular targets using a deeply phenotyped, clinically stratified cohort of cognitively affected and unaffected brain regions from three brain regions of 13 amyotrophic lateral sclerosis patients with the same cognitive screening test performed during life. Using NanoString molecular barcoding as a sensitive mRNA sequencing technique on post‐mortem tissue, we profiled a data‐driven panel of 770 genes using the Neuropathology Panel, followed by region and cell type‐specific validation using BaseScope in situ hybridisation and immunohistochemistry. We identified 50 significantly dysregulated genes that are distinct between cognitively affected and unaffected brain regions. Using BaseScope in situ hybridisation, we also demonstrate that macromolecular complex regulation, notably NLRP3 inflammasome modulation, is a potential, therapeutically targetable, pathological correlate of cognitive resilience in ALS. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd on behalf of The Pathological Society of Great Britain and Ireland.