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Alliance"],"published-print":{"date-parts":[[2019,4]]},"abstract":"<jats:p>\n                    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\n                    <jats:italic>SMN2<\/jats:italic>\n                    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\u2013deleted 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\u2013derived motor neurons and showed protective effects in SMA animal model after intracerebroventricular injection. E64d, another cysteine protease inhibitor which can pass through the blood\u2013brain barrier, showed even more potent therapeutic effects after subcutaneous delivery to SMA mice. Taken together, we have successfully established a human\n                    <jats:italic>SMN2<\/jats:italic>\n                    reporter for future drug discovery and identified the potential therapeutic value of cysteine protease inhibitors in treating SMA via stabilizing SMN proteins.\n                  <\/jats:p>","DOI":"10.26508\/lsa.201800268","type":"journal-article","created":{"date-parts":[[2019,3,25]],"date-time":"2019-03-25T12:55:18Z","timestamp":1553518518000},"page":"e201800268","update-policy":"https:\/\/doi.org\/10.26508\/lsa.crossmarkpolicy","source":"Crossref","is-referenced-by-count":16,"title":["Drug screening with human SMN2 reporter identifies SMN protein stabilizers to correct SMA pathology"],"prefix":"10.26508","volume":"2","author":[{"given":"Yiran","family":"Wang","sequence":"first","affiliation":[{"name":"Brain and Spinal Cord Innovative Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai, 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