Inhibition of the TLR4 receptor prevents neuro-inflammation and degeneration in frataxin-deficient sensory neurons

In FA, specific neurons degenerate, causing problems with movement and coordination. One of the main groups of affected neurons are those responsible for sensing the body’s position, known as proprioceptive sensory neurons (pSNs), found in the dorsal root ganglia of the spinal cord. However, it is not well understood why these particular neurons are so vulnerable in FA. Dr Deepika M Chellapandi is exploring the molecular changes in these neurons when they lack frataxin, using a mouse model that mimics the loss of frataxin in pSNs and analyzing the activity of individual cells before and after the disease symptoms appear. This helped identifying key changes in these neurons, as well as in surrounding support cells known as satellite glial cells (SGCs), which also play a role in the disease. The results revealed that several important pathways that keep neurons healthy, including those related to energy production, calcium balance, and protein synthesis, were disrupted. In addition, she found signs of increased stress and inflammation in the surrounding SGCs. This suggested the involvement of a specific receptor, TLR4, in driving these harmful changes. The aim of this project is to validate the involvement of TLR4 in disease progression and to determine if inhibition of the pathway can help mitigate the disease onset and progression.