{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T01:57:36Z","timestamp":1789610256250,"version":"build-2803163510"},"reference-count":80,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"17","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2022,4,29]]},"abstract":"<jats:p>\n                    Dysfunction and mistrafficking of organelles in autophagy- and endosomal-lysosomal pathways are implicated in neurodegenerative diseases. Here, we reveal selective vulnerability of maturing degradative organelles (late endosomes\/amphisomes) to disease-relevant local calcium dysregulation. These organelles undergo exclusive retrograde transport in axons, with occasional pauses triggered by regulated calcium efflux from agonist-evoked transient receptor potential cation channel mucolipin subfamily member 1 (TRPML1) channels\u2014an effect greatly exaggerated by exogenous agonist mucolipin synthetic agonist 1 (ML-SA1). Deacidification of degradative organelles, as seen after Presenilin 1 (PSEN1) loss of function, induced pathological constitutive \u201cinside-out\u201d TRPML1 hyperactivation, slowing their transport comparably to ML-SA1 and causing accumulation in dystrophic axons. The mechanism involved calcium-mediated c-Jun N-terminal kinase (JNK) activation, which hyperphosphorylated dynein intermediate chain (DIC), reducing dynein activity. Blocking TRPML1 activation, JNK activity, or DIC1B serine-80 phosphorylation reversed transport deficits in\n                    <jats:italic>PSEN1<\/jats:italic>\n                    knockout neurons. Our results, including features demonstrated in Alzheimer-mutant\n                    <jats:italic>PSEN1<\/jats:italic>\n                    knockin mice, define a mechanism linking dysfunction and mistrafficking in lysosomal pathways to neuritic dystrophy under neurodegenerative conditions.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.abj5716","type":"journal-article","created":{"date-parts":[[2022,4,29]],"date-time":"2022-04-29T13:58:46Z","timestamp":1651240726000},"source":"Crossref","is-referenced-by-count":63,"title":["Axonal transport of late endosomes and amphisomes is selectively modulated by local Ca\n                    <sup>2+<\/sup>\n                    efflux and disrupted by PSEN1 loss of function"],"prefix":"10.1126","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5838-958X","authenticated-orcid":true,"given":"Pearl P. Y.","family":"Lie","sequence":"first","affiliation":[{"name":"Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, NY 10962, USA"},{"name":"Department of Psychiatry, New York University Langone Medical Center, New York, NY 10016, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3623-0425","authenticated-orcid":true,"given":"Lang","family":"Yoo","sequence":"additional","affiliation":[{"name":"Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, NY 10962, USA"},{"name":"Department of Psychiatry, New York University Langone Medical Center, New York, NY 10016, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1185-2682","authenticated-orcid":true,"given":"Chris N.","family":"Goulbourne","sequence":"additional","affiliation":[{"name":"Center for Dementia Research, Nathan S. 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Kline Institute, Orangeburg, NY 10962, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0280-8375","authenticated-orcid":true,"given":"Ju-Hyun","family":"Lee","sequence":"additional","affiliation":[{"name":"Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, NY 10962, USA"},{"name":"Department of Psychiatry, New York University Langone Medical Center, New York, NY 10016, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2352-4715","authenticated-orcid":true,"given":"Ralph A.","family":"Nixon","sequence":"additional","affiliation":[{"name":"Center for Dementia Research, Nathan S. 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