Myelin loss in C9orf72 hexanucleotide expansion carriers
The expansion of the intronic GGGGCC repeat (G4C2) in the C9orf72 gene is the most common genetic cause of Frontotemporal Dementia (FTD), Amyotrophic Lateral Sclerosis (ALS) and in the continuum of FTD/ALS. Three pathological mechanisms associated with the presence of this genetic alteration have been described: a loss of function, a toxic gain of function due to the presence of RNA aggregates in the nucleus and a neurotoxic effect due to the generation of small aggregates called dipeptide repeat proteins (DPRs). Another mechanism related to the disease is the presence of inclusions of the phosphorylated protein TDP-43 (transactive response DNA-binding protein-43).
What have be done in this study?
Using postmortem tissue from individuals with FTD carrying the C9orf72 gene expansion, sporadic FTD and controls, and using digital neuropathology, the pattern of different glial markers such as GFAP (astrocytes), Iba1 (microglia) and MBP (myelin) in the frontal cortex and hippocampus has been described and correlated with the main pathological mechanisms described in relation to this genetic alteration: presence of DPRs, presence of RNA aggregates in neuronal nuclei and the presence of TDP-43 inclusions.
The most relevant result obtained in this work was that tissues from patients with the expansion in the C9orf72 gene showed a decrease in MBP protein immunoreactivity in the frontal cortex indicating a loss of myelin. Furthermore, this decrease was associated with the presence of TDP-43 inclusions in this same region.
Relevance of the study
This study describes that there is a specific loss of myelin associated with expansion in the C9orf72 gene.