Whether it is for the billing of a new film, the release of an album, or in the understanding of the pathogenesis of a disease, figuring out who the contributors are and what role they play represents an important first step. In the case of the sporadic neurodegenerative disorder Alzheimer’s Disease (AD), we know that accumulated amyloid β (Aβ) and phosphorylated Tau protein in the brain contribute to disease progression. However, post-mortem mRNA degradation and a lack of cell-specific analysis have limited our ability to further explore disease pathogenesis and uncover potential therapeutic targets.
Now, a team of researchers from the laboratory of Atsushi Iwata (University of Tokyo, Japan) may have supplied the answer: neuron-specific methylome analysis. This strategy exploits post-mortem DNA methylation stability, the purification of AD-related cell types, and high-throughput analysis to provide a DNA methylation map that acts as a rough proxy for transcriptional activity in a cell.
Mano et al. analyzed DNA methylomes from sorted neuronal nuclei from inferior temporal gyrus samples of 30 age-matched control and 30 AD patients with the Infinium 450k methylation array. So what AD-specific contributors did the authors uncover?
- Comparisons between AD and non-AD neurons highlighted eight differentially methylated regions (DMRs) in the genomes of patient samples
- The authors concentrated on the BRCA1 DNA damage repair gene after finding two DMRs in the gene promoter region
- AD neurons displayed BRCA1 promoter hypomethylation and consistently overexpressed BRCA1 protein
- Analysis of AD mouse model neurons also highlighted Brca1 promoter hypomethylation
- Interestingly, the study associated Aβ “burden” with the formation of DNA double-strand breaks (DSBs) and the subsequent induction of BRCA1 expression in vitro and in vivo
- However, BRCA1 protein mislocalized to the cytoplasm, where it formed insoluble co-aggregates with phosphorylated Tau
- As BRCA1 usually localizes to the nucleus where it acts as a DNA damage repair protein, cytoplasmic mislocalization promoted DNA fragmentation
- This genetic instability then prompted a decrease in the number of short neurites and dendritic spines and, therefore, the neuronal dysfunction/impaired synaptic plasticity observed in AD
Overall, this exciting study displays the enormous potential of neuron-specific methylome analysis to uncover factors contributing to AD pathogenesis; however, the authors hope that other neurodegenerative disorders will also benefit from the application of this exciting strategy by revealing potential therapeutic targets.
To discover how neuron-specific methylome analysis could contribute to your studies, head on over to PNAS, October 2017.