Axonal transport of late endosomes and amphisomes is selectively modulated by local Ca²⁺ efflux and disrupted by PSEN1 loss of function.

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

SUBMITTER: Lie PPY 

PROVIDER: S-EPMC9054012 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature