biostudies-literatureLie PPYNIA NIH HHSeabj5716https://www.ebi.ac.uk/biostudies/studies/S-EPMC9054012biostudies-literatureUnknown8(17)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-an 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 "inside-out" TRPML1 hyperactivation, slowing their Science advancesAxonal transport of late endosomes and amphisomes is selectively modulated by local Ca²⁺ efflux and disrupted by PSEN1 loss of function.PMC9054012R01 AG062376Lie PPYHuo CGoulbourne CNStavrides PNixon RAYoo LBerg MJLee JHfalseAxonal transport of late endosomes and amphisomes is selectively modulated by local Ca²⁺ efflux and disrupted by PSEN1 loss of function.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-an 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 "inside-out" TRPML1 hyperactivation, slowing their 2022-01-01T00:00:00Z2022 Apr2025-04-19T09:20:06.664Z2025-04-19T09:20:06.664ZS-EPMC90540123548673010.1126/sciadv.abj5716