The DOI matches its Crossref record; 7 of the 7 references it cites were found in a registry or an index.
Axonal transport of late endosomes and amphisomes is selectively modulated by local Ca 2+ 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 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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Disruption of lysosomal trafficking and maturation in Alzheimer's disease pathology leads not only to cellular stress but also to accumulation of extracellular amyloid β.
“When this lysosomal trafficking and maturation process is disrupted in AD pathology (Lie et al., 2022), it not only leads to cellular stress but also the accumulation of extracellular amyloid β (Aβ) (Lee et al., 2022).”
From Hippocampal TMEM55B overexpression in the 5XFAD mouse model of Alzheimer's disease (2024) · cites this paper as Lie et al., 2022
The endosomal-lysosomal network is dysfunctional in Alzheimer's disease, evident from the accumulation of autophagic vacuoles in the axons of dystrophic neurites due to disruption of retrograde trafficking, acidification and maturation of endo-lysosomes.
“The endosomal-lysosomal network is dysfunctional in Alzheimer's disease (AD), evident from the accumulation of autophagic vacuoles in the axons of dystrophic neurites due to disruption of retrograde trafficking, acidification, and maturation of endo-lysosomes (Gowrishankar et al., 2015;Lie et al., 2022;Sadleir et al., 2016;Serrano-Pozo et al., 2016).”
From Hippocampal TMEM55B overexpression in the 5XFAD mouse model of Alzheimer's disease (2024) · cites this paper as Lie et al., 2022
Presenilin function is disrupted in patients with familial AD mutations in PS.
“Presenilin (PS) function, which is disrupted in patients with familial AD mutations in PS, is associated with dysfunctional lysosomal proteolysis and autophagy (Lee et al., 2010;Lie et al., 2022;Neely et al., 2011;Reddy et al., 2016)”
From Hippocampal TMEM55B overexpression in the 5XFAD mouse model of Alzheimer's disease (2024) · cites this paper as Lie et al., 2022
Presenilin function is associated with dysfunctional lysosomal proteolysis and autophagy.
“Presenilin (PS) function, which is disrupted in patients with familial AD mutations in PS, is associated with dysfunctional lysosomal proteolysis and autophagy (Lee et al., 2010;Lie et al., 2022;Neely et al., 2011;Reddy et al., 2016)”
From Hippocampal TMEM55B overexpression in the 5XFAD mouse model of Alzheimer's disease (2024) · cites this paper as Lie et al., 2022
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Axonal transport deficits and neurodegenerative diseases
Millecamps, S., & Julien, J.-P. (2013) · Nature Reviews Neuroscience · doi:10.1038/nrn3380 · Cited by 755 · cited 1×
“In many cases, on the basis of disease models, transport disruption is thought to be global and to involve microtubule disassembly and/or accumulation of many types of transported cargoes (48, 49).”
Autophagosomes initiate distally and mature during transport toward the cell soma in primary neurons
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Sorted by citations
Mechanisms of autophagy–lysosome dysfunction in neurodegenerative diseases
Nixon, R. A., & Rubinsztein, D. C. (2024) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-024-00757-5 · Cited by 435
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Hippocampal TMEM55B overexpression in the 5XFAD mouse model of Alzheimer's disease
Odfalk, K. F., Wickline, J. L., Smith, S., Dobrowolski, R., & Hopp, S. C. (2024) · Hippocampus · doi:10.1002/hipo.23586 · Cited by 2
Metadata
- Authors
- Lie, P. P. Y., Yoo, L., Goulbourne, C. N., Berg, M. J., Stavrides, P., Huo, C., Lee, J.-H., & Nixon, R. A.
- Affiliations
- Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, NY 10962, USA
- Venue
- Science Advances
- Published
- 2022-04-29
- Volume
- 8
- Issue
- 17
- ISSN
- 2375-2548
- PMC
- PMC9054012
- Cited by
- 63
- References
- 7
- Language
- en
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