| First Author | Lie PPY | Year | 2022 |
| Journal | Sci Adv | Volume | 8 |
| Issue | 17 | Pages | eabj5716 |
| PubMed ID | 35486730 | Mgi Jnum | J:338551 |
| Mgi Id | MGI:7275864 | Doi | 10.1126/sciadv.abj5716 |
| Citation | Lie PPY, et al. (2022) Axonal transport of late endosomes and amphisomes is selectively modulated by local Ca(2+) efflux and disrupted by PSEN1 loss of function. Sci Adv 8(17):eabj5716 |
| abstractText | 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. |
