TLR4-mediated neuroimmune signalling drives proprioceptive neuron degeneration in Friedreich ataxia

Friedreich ataxia (FA) is one of the most common inherited autosomal recessive neurodegenerative disorder, caused by a GAA repeat expansion in the FXN gene, leading to frataxin deficiency and progressive sensory and spinocerebellar ataxia. FA is characterized by selective vulnerability of proprioceptive sensory neurons (pSNs) in the dorsal root ganglia (DRG), which are major contributors to sensory ataxia. Despite the central role of mitochondrial dysfunction in FA, the mechanisms that drives the neuronal loss remains unclear. Here, we show that metabolic stress in sensory neurons elicits a neuroimmune response in surrounding tissue, revealing a non-cell-autonomous mechanism of disease progression. We identify Toll-like receptor 4 (TLR4) signaling as a key link between neuronal dysfunction and inflammatory response. Inhibition of TLR4 reduces cellular stress, restores neuronal integrity, and delays disease progression in vivo. These findings redefine FA as a disorder involving neuroimmune crosstalk and highlight TLR4 signaling as a potential therapeutic target.