Frataxin deficiency in proprioceptive neurons is causal to inflammatory and glial responses in dorsal root ganglia

Abstract

Friedreich ataxia (FA), the most common recessive hereditary ataxia, is an early-onset neurodegenerative disease characterized by pathological changes occurring first in the peripheral dorsal root ganglia (DRG), with loss of the large sensory proprioceptive neurons, leading to ganglionopathy and proprioceptive deficits. FA is caused by a mutation in frataxin gene (Fxn), leading to reduced expression of frataxin protein (FXN), an essential ubiquitous mitochondrial protein. Most research has focused on the pathophysiological involvement of proprioceptors. However, in recent years, neuroinflammation is increasingly recognized as an integral and critical contributor in FA pathogenesis. Furthermore, it has also recently been shown a primary reactivity of satellite glial cells (SGCs; glia tightly enwrapping proprioceptor cell bodies), suggesting a role of inflammation and SGC responses in the destruction of proprioceptors in FA patients' DRGs. It remains unclear to what extent the increase in DRG macrophage response and/or SGC reactivity may contribute to FA phenotype. Therefore, it is important to fully study and understand the mechanism of proprioceptor-macrophages-SGC interactions and their regulations. Exploring relationship between these three cell types has profound implications for breaking through the limitation of treatment of FA. Here we asked whether FXN deficiency selectively in DRG proprioceptive neurons is sufficient to cause inflammatory and glial responses found in patients' DRG. We used RNA profiling, bioinformatics signaling network and pathway analysis, combined with immunohistochemistry and behavioral experiments to reveal some genes, signaling pathways in macrophages and SGCs that may represent potential biomarkers of the disease. Our study revealed that proprioceptor FXN deficiency causes major changes in inflammatory macrophage and SGC gene transcription as well as macrophage and SGC number, highlighting molecular and cellular pathways that were sequentially altered, thus representing temporal signatures of FA ganglionopathy progression.