Article ; Online: Axonal transport of late endosomes and amphisomes is selectively modulated by local Ca
2022 Volume 8, Issue 17, Page(s) eabj5716
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- ... ...
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 |
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Language | English |
Publishing date | 2022-04-29 |
Publishing country | United States |
Document type | Journal Article |
ZDB-ID | 2810933-8 |
ISSN | 2375-2548 ; 2375-2548 |
ISSN (online) | 2375-2548 |
ISSN | 2375-2548 |
DOI | 10.1126/sciadv.abj5716 |
Database | MEDical Literature Analysis and Retrieval System OnLINE |
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