Amyotrophic lateral sclerosis ALS is an incurable fatal paralytic disease that affects adults. ALS ischaracterized by the degeneration of the motor neurons innervating the muscles. Our proposal investigated the neuroprotective effect and therapeutic value of a drug the translocator protein TSPO ligand PK11195 PK, which we found to be very promising in cell models of ALS. These models take into consideration that in ALS, motor neurons are killed by neighboring cells called astrocytes, which transform from supportive to neurotoxic cells. Over these two years of the award, we were able to meet our main objectives. First, in our cell study, we found that PK acts directly on motor neurons to prevent their death, not via the astrocytes. Then, we evidenced that PK protects not only the motor neuron cell bodies, but also their long axons. We also found that TSPO is not expressed in the same cell compartments in motor neurons and astrocytes, suggesting cell-specific roles. Finally, we demonstrated that PK is not neuroprotective by inhibiting TSPO. In contrast, an increase in TSPO content may protect motor neurons against ALS. Second, in our preclinical study in ALS mice, we have determined that the best route to administer PK is continuous delivery via osmotic mini-pumps placed under the skin of the animals. We tested two doses of PK, well tolerated by the mice both allow PK to reach desirable brain and spinal cord levels. Overall we found that both doses of PK significantly improve grip strength, motor performance, and muscle innervation of ALS mice in the early phase of the disease. However, PK does not delay the onset of paralysis and does not appear to protect motor neuron survival or extend mouse lifespan at later disease stages. In diseased ALS mouse spinal cord, we found that TSPO expression was primarily co-localized with inflammatory reactive astrocytes.