Collectively, our data suggest that a missense mutation (V91M) in TREX1 causes the activation of ER stress and the UPR, which in turn results in neurodegeneration through the disruption of ER Ca2+ homeostasis and/or the Golgi-microtubule network and thereby contributes to the progression of HSP. The gene discussed is TREX1; the disease is hereditary spastic paraplegia.