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A number of studies have now demonstrated that ER-mitochondria signaling is perturbed in these diseases and there is evidence that this may be a driving mechanism in disease onset and progression. VAPB and PTPIP51 are ER-mitochondria tethering proteins; VAPB is an ER protein and PTPIP51 is an outer mitochondrial membrane protein and the two proteins interact to enable inter-organelle signaling. The VAPB-PTPIP51 interaction is disrupted in Alzheimer\u2019s disease, Parkinson\u2019s disease, FTD and ALS. Here we review the roles of VAPB and PTPIP51 in ER-mitochondria signaling and the mechanisms by which neurodegenerative disease insults may disrupt the VAPB-PTPIP51 interaction.<\/jats:p>","DOI":"10.1186\/s40478-025-01964-7","type":"journal-article","created":{"date-parts":[[2025,3,5]],"date-time":"2025-03-05T07:53:11Z","timestamp":1741161191000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Structural and functional studies of the VAPB-PTPIP51 ER-mitochondria tethering proteins in neurodegenerative diseases"],"prefix":"10.1186","volume":"13","author":[{"given":"Kerry","family":"Blair","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raquel","family":"Martinez-Serra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Gosset","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra M.","family":"Mart\u00edn-Guerrero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00e1bor M.","family":"M\u00f3rotz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Atherton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline C.","family":"Mitchell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Markovinovic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher C. 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