De Pace R, Ghosh S, Ryan VH, Sohn M, Jarnik M, Rezvan Sangsari P, Morgan NY, Dale RK, Ward ME, Bonifacino JS. Messenger RNA transport on lysosomal vesicles maintains axonal mitochondrial homeostasis and prevents axonal degeneration. Nat Neurosci. 2024 Jun;27(6):1087-1102. Epub 2024 Apr 10 PubMed.
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Tel-Aviv University
I thoroughly enjoyed reading this manuscript, especially its elucidation of a groundbreaking mechanism crucial for maintaining axonal homeostasis. The study sheds light on the key role of lysosome-related vesicles in transporting and localizing specific mRNAs into axons far from the cell body, highlighting their significance in maintaining axonal homeostasis and the role that axonal transport and local synthesis events play in spatiotemporal signaling, metabolic events, and axonal mitochondria maintenance.
Through the innovative approach of BORC knockout, the study uncovers a subset of axonal mRNAs, notably those encoding ribosomal and mitochondrial proteins, that depend on this transport mechanism. The depletion of these mRNAs results in mitochondrial abnormalities and eventually leads to axonal degeneration, reminiscent of pathways implicated in diverse neurodegenerative conditions. These findings underscore the importance of understanding the basic mechanism of mRNA transport and localization and offer insights into potential mechanisms underlying axon degeneration and neurodegeneration, offering possible new avenues for therapeutic exploration.
View all comments by Eran PerlsonKULeuven & VIB
This is an exciting study by Juan Bonifacino’s group where they explored the regulation and importance of the BORC adaptor complex in axonal transport of lysosomes using new BORC-deficient iPSC-derived human neurons. Whereas the role of lysosomes has been extended from “degradation bins” to a central signaling hub to maintain cellular (and neuronal) homeostasis, it is more recently appreciated that some RNA granules use lysosomes and late endosomes for hitchhiking. This is particularly relevant in neurons, which have decentralized their translation machinery, allowing local translation in distal axonal regions. In this way, neurons can more rapidly respond to the dynamics of synaptic changes, which requires the presence of functional mitochondria.
Through an impressive number of high-quality assays and analyses in mature neurons, the Bonifacino group now demonstrates that an important aspect of the transported RNA transcripts relates to critical mitochondrial functions, such as oxidative phosphorylation: If the neuron does not succeed in “feeding” its distal ends with RNA granules, this strongly affects mitochondrial fitness, impacting on lysosomal/autophagy homeostasis and resulting in a neurodegenerative phenotype. While the authors connect this to rare neurodevelopmental/neurodegenerative disorders, it likely occurs in the broader range of neurodegenerative diseases. This has been demonstrated previously by the group of Michael Ward, who identified mutations in AnnexinA11, causing ALS, that impact the efficiency of lysosomes to deliver RNA granules to distal axons (Liaio et al., 2019).
More broadly, this study may contribute to an alternative understanding of the role of mitochondrial dysfunction in neurodegenerative diseases, including Alzheimer’s and Parkinson’s diseases. Whereas genetics is increasingly identifying risk loci and genes linked to endosomal and lysosomal functions (for instance Van Acker et al., 2019; Van Acker et al., 2021), genetic evidence for a primary causal role of mitochondrial defects appears to be scarcer. But this paper provides a mechanism by which mitochondrial defects can clearly occur downstream of lysosomal dyshomeostasis, propagating defects to other organelles, and ultimately leading to neuronal degeneration.
References:
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