[220603 Àú³Î¹ßÇ¥] Axonal transport of late endosomes and amphisomes is selectively modulated by local Ca2+ efflux and disrupted by PSEN1 loss of function À̵¿ÁØ ¦¢ 2022-06-03 HIT 49977 |
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Sci Adv. 2022 Apr; 8(17): eabj5716. Published online 2022 Apr 29. doi: 10.1126/sciadv.abj5716 PMCID: PMC9054012 PMID: 35486730 Axonal transport of late endosomes and amphisomes is selectively modulated by local Ca2+ efflux and disrupted by PSEN1 loss of functionAssociated DataAbstractDysfunction 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 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 PSEN1 knockout neurons. Our results, including features demonstrated in Alzheimer-mutant PSEN1 knockin mice, define a mechanism linking dysfunction and mistrafficking in lysosomal pathways to neuritic dystrophy under neurodegenerative conditions. |
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