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

• Published in: Science advances Vol. 8; no. 17; p. eabj5716
• Main Authors: Lie, Pearl P Y, Yoo, Lang, Goulbourne, Chris N, Berg, Martin J, Stavrides, Philip, Huo, Chunfeng, Lee, Ju-Hyun, Nixon, Ralph A
• Format: Journal Article
• Language: English
• Published: American Association for the Advancement of Science 29.04.2022
• Subjects: Cellular Neuroscience; Diseases and Disorders; Neuroscience; SciAdv r-articles
• ISSN: 2375-2548
• DOI: 10.1126/sciadv.abj5716

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. Dysfunctional degradative organelles abnormally release Ca 2+ that slows their axonal transport, promoting AD-like dystrophy.