Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease involving progressive loss of upper and lower motor neurons, often linked with frontotemporal dementia (FTD), forming the ALS-frontotemporal spectrum disorder (ALS-FTSD). Mutations associated with ALS-FSTD arise from hexanucleotide repeat expansions (HREs) in the C9orf72 gene. It is imperative to better analyze and define heterogeneity along this spectrum of mutations to work toward more effective treatment strategies. One approach is to analyze linked molecular factors and dysregulated neuroinflammatory panel signatures (NPS) in post-mortem motor cortex tissue from clinically diverse C9-ALS-FTSD cases.
In a December 2023 publication in Brain, Rifai et al. identified 20 dysregulated genes in C9-ALS-FTSD with an enrichment of microglial and inflammatory response pathways by using a targeted NanoString molecular barcoding approach that analyzed 770 genes in an nCounter neuroinflammation panel. Biotium’s RNAstorm™ FFPE RNA Extraction Kit was used to extract RNA from 33 samples of post-mortem brain tissue with ALS-FTSD obtained from the Medical Research Council (MRC) Edinburgh Brain Bank. Two genes, FKBP5 and brain-derived neurotrophic factor (BDNF), were selected for validation due to their correlations with cognitive function and disease duration, respectively, and it was confirmed that individuals with longer disease duration express higher levels of BDNF mRNA. Two distinct neuroinflammatory panel signatures (NPS), NPS1 and NPS2, were also found to delineate distinct disease subgroups. Comparison of NPS between C9-ALS-FTSD cases and those from sporadic ALS and SOD1-ALS cohorts revealed consistent patterns, independent of genetic or external factors. These findings underscore the importance of effectively tailoring therapeutic approaches based on distinct molecular signatures within and between ALS-FTSD cohorts.
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Full Citation
Rifai, O.M., O’Shaughnessy, J., et al (2023) Distinct neuroinflammatory signatures exist across genetic and sporadic amyotrophic lateral sclerosis cohorts (2023). Brain, Volume 146, Issue 12, 2023, 5124–5138, DOI: 10.1093/brain/awad243