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The objective of this study was to further investigate the role of\n                      <jats:italic>SMPD1<\/jats:italic>\n                      mutations in PD.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      <jats:italic>SMPD1<\/jats:italic>\n                      was sequenced in 3 cohorts (Israel Ashkenazi Jewish cohort, Montreal\/Montpellier, and New York), including 1592 PD patients and 975 controls. Additional data were available for 10,709 Ashkenazi Jewish controls. Acid\u2010sphingomyelinase activity was measured by a mass spectrometry\u2010based assay in the New York cohort. \u03b1\u2010Synuclein levels were measured in vitro following CRISPR\/Cas9\u2010mediated knockout and siRNA knockdown of SMPD1 in HeLa and BE(2)\u2010M17 cells. Lysosomal localization of acid\u2010sphingomyelinase with different mutations was studied, and in silico analysis of their effect on acid\u2010sphingomyelinase structure was performed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      <jats:italic>SMPD1<\/jats:italic>\n                      mutations were associated with PD in the Ashkenazi Jewish cohort, as 1.4% of PD patients carried the p.L302P or p.fsP330 mutation, compared with 0.37% in 10,709 Ashkenazi Jewish controls (OR, 3.7; 95%CI, 1.6\u20108.2;\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.0025). In the Montreal\/Montpellier cohort, the p.A487V variant was nominally associated with PD (1.5% versus 0.14%;\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.0065, not significant after correction for multiple comparisons). Among PD patients, reduced acid\u2010sphingomyelinase activity was associated with a 3.5\u2010 to 5.8\u2010year earlier onset of PD in the lowest quartile versus the highest quartile of acid\u2010sphingomyelinase activity (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.01\u20100.001). We further demonstrated that\n                      <jats:italic>SMPD1<\/jats:italic>\n                      knockout and knockdown resulted in increased \u03b1\u2010synuclein levels in HeLa and BE(2)\u2010M17 dopaminergic cells and that the p.L302P and p.fsP330 mutations impair the traffic of acid\u2010sphingomyelinase to the lysosome.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Our results support an association between\n                      <jats:italic>SMPD1<\/jats:italic>\n                      variants, acid\u2010sphingomyelinase activity, and PD. Furthermore, they suggest that reduced acid\u2010sphingomyelinase activity may lead to \u03b1\u2010synuclein accumulation. \u00a9 2019 International Parkinson and Movement Disorder Society\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/mds.27642","type":"journal-article","created":{"date-parts":[[2019,2,20]],"date-time":"2019-02-20T22:08:51Z","timestamp":1550700531000},"page":"526-535","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":118,"title":["<i>SMPD1<\/i>\n                    mutations, activity, and \u03b1\u2010synuclein accumulation in Parkinson's disease"],"prefix":"10.1002","volume":"34","author":[{"given":"Roy N.","family":"Alcalay","sequence":"first","affiliation":[{"name":"Department of Neurology, College of Physicians and Surgeons Columbia University  New York NY USA"},{"name":"Taub Institute for Research on Alzheimer's Disease and the Aging Brain Columbia University  New York NY 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