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Lie PP, Yoo L, Goulbourne CN, Berg MJ, Stavrides P, Huo C, Lee JH, Nixon RA. Axonal transport of late endosomes and amphisomes is selectively modulated by local Ca2+ efflux and disrupted by PSEN1 loss of function. Sci Adv. 2022 Apr 29;8(17):eabj5716. PubMed.
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Rosalind Franklin University/The Chicago Medical School
This study is an important extension in a series of mechanistic studies from the Nixon lab detailing how misregulation of lysosome through PS or Ca2+ deficits contribute to key features of AD. The value of this study lies in the intricate linkage of PS deficits, either in model cells or AD mouse models, which impedes proper construction of the vATPase proton pump, and thus impairs proper acidification of lysosomes.
This result in deficits in autophagosome degradation and excess calcium release from lysosome through pH-regulated TRPML1 channels. The authors revealed that the excess calcium-triggered kinase activity hyperphosprylated dynein components and slowed, or interfered with, retrograde transport, contributing to the dystrophic neurites that are characteristic of AD cellular pathology.
This study stands out as a needed piece in the cell biology puzzle of AD, a field which pulls heavily from genetics and end-point proteinopathy studies, but would greatly benefit from more functional and mechanistic studies such as this to delineate how these gene-level changes directly contribute to AD phenotypes, and specifically how the defining protein aggregates and cellular pathophysiology arise.
During this exciting time of deep transcriptomics and revelations in gene-level changes in AD, this series of studies from the Nixon lab has ticked many of these boxes, tracing the pathway from PS mutations or loss of function, to lysosome de-acidification, calcium dysregulation, protein mishandling and trafficking deficits. Each of these points in the path can further amplify and spin off additional pathogenic cascades, thus creating a network of seemingly disparate features that share common upstream sources.
It would further solidify the study to know more regarding the nature, role, and status of the endogenous activators of TRPML1, as well as additional consequences of the altered calcium release, but given the depth and compelling detail of the current findings, these remaining questions would likely fill another complete study.
View all comments by Grace StutzmannTel Aviv University
The mechanisms by which Presenilin mutations lead to Alzheimer’s disease pathogenesis remains somewhat elusive. In previous work, Ralph Nixon’s group showed that lack of PSEN1 in neurons impairs lysosomal acidification resulting in deleterious effects produced by uncontrolled calcium efflux through hyperactivation of TRMP1, an ion channel in the lysosome.
In this new paper, the group further investigated the molecular mechanism underling axon degeneration mediated by impaired acidification of the lysosomal organelles, and its potential relation to PSEN1. Apparently, reduced acidification of late endosomes/amphisomes disturbs their retrograde cellular transport mediated by the motor protein dynein. In this signaling cascade scenario, de-acidification results in “inside-out” activation of TRMP1, leading to persistent calcium efflux, activation of c-Jun N-terminal kinase (JNK), and aberrant phosphorylation of dynein that slows down retrograde transport.
Lack of PSEN1 in PSEN1 knockout neurons copied theses effects, thus implicating PSEN1 dysfunction in impaired retrograde motility of de-acidified organelles. Hence, insufficient transport of the lysosomal system vesicles represents a major cause of axon degeneration.
However, the use of PSEN1 KO systems in most of their studies raises a concern of the relevance of these results to AD that rather express PSEN1mutants. The authors addressed this question by using a mouse model expressing familial AD PSEN1 mutant. A similar phenomenon was observed in the mouse brains, which exhibited dystrophic neurites, de-acidified lysosomes, and accumulated degradative organelles, although these observations were age-dependent.
An important aspect of this work is its broad implications to neurodegenerative disorders, linking acidification failure in the lysosome pathway with axonal dystrophy. An interesting question in this respect is whether de-acidification of lysosomes imposed by other signaling components would result in a similar signaling cascade. For example, the kinase, GSK-3, an important drug discovery target in AD, has been shown to impair lysosomal acidification via the mTORC1/autophagy pathways. It will be interesting to examine if hyperactive GSK-3, often seen in AD conditions, impairs lysosome-organelles cellular traffic via its ability to de-acidify lysosomes.
View all comments by Hagit Eldar-FinkelmanMake a Comment
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