This includes Siponimod (4), a selective S1P1 and S1P5 modulator that has been recently approved for the treatment of MS, especially for the active secondary progressive form of the disease.12 However, the exact mechanism of action of compounds such as siponimod is still unclear and thus, tool compounds are required to fully understand the effects of S1P5 modulation and how this relates to neurodegenerative disease. This evidence concerns the gene S1PR5 and neurodegenerative disease.