Abstract
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 language | English |
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Pages (from-to) | 262-268 |
Number of pages | 7 |
Journal | The Journal of pathology |
Volume | 256 |
Early online date | 6 Jan 2022 |
DOIs | |
Publication status | Published - Mar 2022 |
Bibliographical note
FundingPathological Society of Great Britain and Ireland. Grant Number: Jean Shanks Foundation Clinical Lecturer Support G
OR is funded by a Wellcome Trust PhD fellowship (108890/Z/15/Z). JMG is funded by a starter grant for clinical lecturers from the AMS (210JMG 3102 R45620) and a Clinical Lecturer Support Grant from The Pathological Society/Jean Shanks Foundation, and brain bank funding from the MRC (MR/L016400/1). EE is funded by a PhD fellowship from the CSO and MND Scotland: 217ARF R45951.
Keywords
- cognition
- amyotrophic lateral sclerosis;
- NLRP3 inflammasome
- interleukin 6
- nterleukin 10
- SIRT2