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[220603 저널발표] Axonal transport of late endosomes and amphisomes is selectively modulated by local Ca2+ efflux and disrupted by PSEN1 loss of function

이동준 │ 2022-06-03

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47174

 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 function

Pearl P. Y. LieConceptualizationFormal analysisInvestigationMethodologyProject administrationValidationVisualizationWriting - original draftWriting - review & editing, 1 , 2 , Lang YooConceptualizationData curationFormal analysisInvestigationProject administrationResourcesValidationVisualizationWriting - review & editing, 1 , 2 , Chris N. GoulbourneInvestigationResourcesValidationVisualization, 1 Martin J. BergFormal analysisInvestigationValidationVisualization, 1 Philip StavridesInvestigationSoftwareValidation, 1 Chunfeng HuoResourcesValidation, 1 Ju-Hyun LeeInvestigationValidationVisualization, 1 , 2 and Ralph A. NixonConceptualizationFunding acquisitionInvestigationMethodologyProject administrationResourcesSupervisionValidationVisualizationWriting - review & editingcorresponding author 1 , 2 , 3 , 4 ,*

Abstract

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 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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