Tubulointerstitial nephritis antigen-like 1 (Tinagl1), as a secreted matricellular protein, are implicated in the modulation of diverse processes including cell survival. We previously created transgenic mice expressing a phosphorylation-defective mutant of succinate dehydrogenase A (SDHA^Y215F) in astrocytes for evaluation of the effects of mitochondrial ROS on astrocyte reactivity and showed that reactive astrocytes induce dopaminergic neuronal loss though the expression of Tinagl1 in substantia nigra. In the present study, we investigate the effect of glial-derived Tinagl1 on neuronal survival. Conditioned medium prepared from primary astrocytes expressing either SDHA^Y215F or Tinagl1 significantly decreased the number of microtubule associated protein 2-positive cells as compared with control medium in primary neuron culture. Furthermore, recombinant Tinagl1 (rTinagl1) also significantly induced neuronal apoptosis in a dose-dependent manner. Signaling analysis revealed that rTinagl1 inhibits Akt activation, whereas promotes MKK4 activation in primary neuron culture. These results suggest that glial-derived Tinagl1 may regulate neuronal survival through modulation of Akt and MKK4 signaling. Exact molecular targets for Tinagl1 will be discussed.