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The triggers for neurodegeneration in FTD with <jats:italic>GRN<\/jats:italic> (FTD-<jats:italic>GRN<\/jats:italic>) or <jats:italic>C9orf72<\/jats:italic> (FTD-<jats:italic>C9orf72<\/jats:italic>) gene abnormalities are unknown, although evidence from mouse and cell culture models suggests that <jats:italic>GRN<\/jats:italic> mutations disrupt lysosomal lipid catabolism. To determine how brain lipid metabolism is affected in familial FTD with TDP-43 inclusions, and how this is related to myelin and lysosomal markers, we undertook comprehensive lipidomic analysis, enzyme activity assays, and western blotting on grey and white matter samples from the heavily-affected frontal lobe and less-affected parietal lobe of FTD-<jats:italic>GRN<\/jats:italic> cases, FTD-<jats:italic>C9orf72<\/jats:italic> cases, and age-matched neurologically-normal controls. Substantial loss of myelin-enriched sphingolipids (sulfatide, galactosylceramide, sphingomyelin) and myelin proteins was observed in frontal white matter of FTD-<jats:italic>GRN<\/jats:italic> cases. A less-pronounced, yet statistically significant, loss of sphingolipids was also observed in FTD-<jats:italic>C9orf7<\/jats:italic>2. FTD-<jats:italic>GRN<\/jats:italic> was distinguished from FTD-<jats:italic>C9orf72<\/jats:italic> and control cases by increased acylcarnitines in frontal grey matter and marked accumulation of cholesterol esters in both frontal and parietal white matter, indicative of myelin break-down. Both FTD-<jats:italic>GRN<\/jats:italic> and FTD-<jats:italic>C9orf72<\/jats:italic> cases showed significantly increased lysosomal and phagocytic protein markers, however galactocerebrosidase activity, required for lysosomal catabolism of galactosylceramide and sulfatide, was selectively increased in FTD-<jats:italic>GRN<\/jats:italic>. We conclude that both <jats:italic>C9orf72<\/jats:italic> and <jats:italic>GRN<\/jats:italic> mutations are associated with disrupted lysosomal homeostasis and white matter lipid loss, but <jats:italic>GRN<\/jats:italic> mutations cause a more pronounced disruption to myelin lipid metabolism. Our findings support the hypothesis that hyperactive myelin lipid catabolism is a driver of gliosis and neurodegeneration in FTD-<jats:italic>GRN<\/jats:italic>. Since FTD-<jats:italic>GRN<\/jats:italic> is associated with white matter hyperintensities by MRI, our data provides important biochemical evidence supporting the use of MRI measures of white matter integrity in the diagnosis and management of FTD.<\/jats:p>","DOI":"10.1186\/s40478-023-01544-7","type":"journal-article","created":{"date-parts":[[2023,3,26]],"date-time":"2023-03-26T23:03:44Z","timestamp":1679871824000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":52,"title":["Disrupted myelin lipid metabolism differentiates frontotemporal dementia caused by GRN and C9orf72 gene mutations"],"prefix":"10.1186","volume":"11","author":[{"given":"Oana C.","family":"Marian","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan D.","family":"Teo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun Yup","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huitong","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John B.","family":"Kwok","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramon","family":"Landin-Romero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Glenda","family":"Halliday","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1655-1184","authenticated-orcid":false,"given":"Anthony S.","family":"Don","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,3,27]]},"reference":[{"key":"1544_CR1","doi-asserted-by":"publisher","unstructured":"Olney NT, Spina S, Miller BL (2017) Frontotemporal Dementia. 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Since the research used post-mortem brain bank tissue samples obtained from the Sydney Brain Bank and NSW Brain Tissue Resource Centre, consent to participate is not required.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}}],"article-number":"52"}}