About 90% of the amyotrophic lateral sclerosis (ALS) cases are seemingly “sporadic” without a family history of disease. With hundreds of distinct variants in more than a dozen genes contributing to disease risk, it is hard to identify disease associated signatures and biomarkers. The most common genetic contributor to ALS is a hexanucleotide (GGGGCC) repeat expansion within the first intron of C9ORF72. The same gene signature is also associated with frontotemporal dementia (FTD), however how it contributes to the disease development is not clear. Through analyses of RNA-sequencing data from C9ORF72 and sporadic patients, and validations in a large ALS/FTLD patient cohort and gain-of-function models, Eggan Lab has identified distinct transcriptional signatures reflective of C9ORF72-specific pathogenesis. The findings specifically link these signatures to the activation of the highly conserved HSF1 pathway that mediates the compensatory response to disruptions in proteostasis, such as heat shock. HSF1 impairment and loss of function has been reported in age-related neurodegeneration such as Huntington’s, and pharmacological activation of HSF1 has been proposed as a therapeutic strategy to enhance protein chaperone function and neuronal survival in neurodegenerative disease. Surprisingly, Eggan Lab provides the first evidence of increased, rather than impaired, activity of HSF1, by analyzing human brain samples for a specific neurodegenerative disease. This activation was also found to be directly linked to presence of toxic dipeptide repeat proteins (DPRs) that are translated from the hexanucleotide repeats.
Characterizing the transcriptional response that occurs in various brain regions in ALS and FTD patients has the potential to provide useful insights into whether genetic subgroups of patients display common or divergent mechanisms, and for validating proposed mechanisms through which mutations act. These findings provide multiple potential biomarkers for insightful categorization of ALS and dementia patients that could reveal signatures for the defective pathway and guide development and administration of appropriate therapeutic strategies.