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Fox Foundation and the Queen Elisabeth Medical Foundation for Neurosciences"},{"name":"Ernest Solvay Award"},{"name":"Research Foundation Flanders PhD fellowship","award":["11Y7518N"],"award-info":[{"award-number":["11Y7518N"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Acta Neuropathol"],"published-print":{"date-parts":[[2020,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Parkinson\u2019s disease (PD) is a progressive neurodegenerative brain disease presenting with a variety of motor and non-motor symptoms, loss of midbrain dopaminergic neurons in the substantia nigra pars compacta and the occurrence of \u03b1-synuclein-positive Lewy bodies in surviving neurons. Here, we performed whole exome sequencing in 52 early-onset PD patients and identified 3 carriers of compound heterozygous mutations in the ATP10B P4-type ATPase gene. Genetic screening of a Belgian PD and dementia with Lewy bodies (DLB) cohort identified 4 additional compound heterozygous mutation carriers (6\/617 PD patients, 0.97%; 1\/226 DLB patients, 0.44%). We established that\n                    <jats:italic>ATP10B<\/jats:italic>\n                    encodes a late endo-lysosomal lipid flippase that translocates the lipids glucosylceramide (GluCer) and phosphatidylcholine (PC) towards the cytosolic membrane leaflet. The PD associated ATP10B mutants are catalytically inactive and fail to provide cellular protection against the environmental PD risk factors rotenone and manganese. In isolated cortical neurons, loss of ATP10B leads to general lysosomal dysfunction and cell death. Impaired lysosomal functionality and integrity is well known to be implicated in PD pathology and linked to multiple causal PD genes and genetic risk factors. Our results indicate that recessive loss of function mutations in\n                    <jats:italic>ATP10B<\/jats:italic>\n                    increase risk for PD by disturbed lysosomal export of GluCer and PC. Both ATP10B and glucocerebrosidase 1, encoded by the PD risk gene\n                    <jats:italic>GBA1<\/jats:italic>\n                    , reduce lysosomal GluCer levels, emerging lysosomal GluCer accumulation as a potential PD driver.\n                  <\/jats:p>","DOI":"10.1007\/s00401-020-02145-7","type":"journal-article","created":{"date-parts":[[2020,3,14]],"date-time":"2020-03-14T06:02:54Z","timestamp":1584165774000},"page":"1001-1024","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":69,"title":["Mutated ATP10B increases Parkinson\u2019s disease risk by compromising lysosomal glucosylceramide export"],"prefix":"10.1007","volume":"139","author":[{"name":"The BELNEU consortium","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaun","family":"Martin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie","family":"Smolders","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris","family":"Van den Haute","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bavo","family":"Heeman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"van Veen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Crosiers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Igor","family":"Beletchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aline","family":"Verstraeten","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helena","family":"Gossye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00e9raldine","family":"Gelders","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Pals","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norin Nabil","family":"Hamouda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastiaan","family":"Engelborghs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Jacques","family":"Martin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Eggermont","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter Paul","family":"De Deyn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Cras","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veerle","family":"Baekelandt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Vangheluwe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0183-7665","authenticated-orcid":false,"given":"Christine","family":"Van Broeckhoven","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,3,14]]},"reference":[{"key":"2145_CR1","doi-asserted-by":"publisher","first-page":"1255","DOI":"10.1002\/mds.20527","volume":"20","author":"D Aarsland","year":"2005","unstructured":"Aarsland D, Zaccai J, Brayne C (2005) A systematic review of prevalence studies of dementia in Parkinson's disease. 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