RT Journal Article SR Electronic T1 Drug screening with human SMN2 reporter identifies SMN protein stabilizers to correct SMA pathology JF Life Science Alliance JO Life Sci. Alliance FD Life Science Alliance LLC SP e201800268 DO 10.26508/lsa.201800268 VO 2 IS 2 A1 Yiran Wang A1 Chongchong Xu A1 Lin Ma A1 Yongchao Mou A1 Bowen Zhang A1 Shanshan Zhou A1 Yue Tian A1 Jessica Trinh A1 Xiaoqing Zhang A1 Xue-Jun Li YR 2019 UL https://www.life-science-alliance.org/content/2/2/e201800268.abstract AB Spinal muscular atrophy (SMA), the leading genetic cause of infant mortality, is caused by reduced levels of functional survival motor neuron (SMN) protein. To identify therapeutic agents for SMA, we established a versatile SMN2-GFP reporter line by targeting the human SMN2 gene. We then screened a compound library and identified Z-FA-FMK as a potent candidate. Z-FA-FMK, a cysteine protease inhibitor, increased functional SMN through inhibiting the protease-mediated degradation of both full-length and exon 7–deleted forms of SMN. Further studies reveal that CAPN1, CAPN7, CTSB, and CTSL mediate the degradation of SMN proteins, providing novel targets for SMA. Notably, Z-FA-FMK mitigated mitochondriopathy and neuropathy in SMA patient–derived motor neurons and showed protective effects in SMA animal model after intracerebroventricular injection. E64d, another cysteine protease inhibitor which can pass through the blood–brain barrier, showed even more potent therapeutic effects after subcutaneous delivery to SMA mice. Taken together, we have successfully established a human SMN2 reporter for future drug discovery and identified the potential therapeutic value of cysteine protease inhibitors in treating SMA via stabilizing SMN proteins.