Quantitative transportomics identifies Kif5a as a major regulator of neurodegeneration
- Stanford University, United States
- The Scripps Research Institute, United States
- Johns Hopkins University School of Medicine, United States
Abstract
Many neurons in the adult central nervous system, including retinal ganglion cells (RGCs), degenerate and die after injury. Early axon protein and organelle trafficking failure is a key component in many neurodegenerative disorders yet changes to axoplasmic transport in disease models have not been quantified. We analyzed early changes in the protein 'transportome' from (RGC somas to their axons after optic nerve injury and identified transport failure of an anterograde motor protein Kif5a early in RGC degeneration. We demonstrated that manipulating Kif5a expression affects anterograde mitochondrial trafficking in RGCs and characterized axon transport in Kif5a knockout mice to identify proteins whose axon localization was Kif5a-dependent. Finally, we found that knockout of Kif5a in RGCs resulted in progressive RGC degeneration in the absence of injury. Together with expression data localizing Kif5a to human RGCs, these data identify Kif5a transport failure as a cause of RGC neurodegeneration and point to a mechanism for future therapeutics.
Data availability
All data generated during this study are included in the manuscript and supporting source files in excel format. Source data files have been provided for Figures 1, 4, 5 and Supplementary Figure 2.
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scRNA-seq of the developing human retinaNCBI Gene Expression Omnibus, GSE138002.
Article and author information
Author details
John R Yates III III
Jeffrey L Goldberg
Funding
National Institutes of Health (EY011261)
- Hollis T Cline
Research to Prevent Blindness
- Jeffrey L Goldberg
National Institutes of Health (U01EY027261)
- John R Yates III III
- Hollis T Cline
- Jeffrey L Goldberg
National Institutes of Health (EY027437)
- Hollis T Cline
National Institutes of Health (P30 EY019005)
- Hollis T Cline
National Institutes of Health (R01MH103134)
- Hollis T Cline
National Institutes of Health (P41 GM103533)
- John R Yates III III
Hahn Family Foundation
- Hollis T Cline
National Institutes of Health (R01MH067880)
- John R Yates III III
National Institutes of Health (P30 EY026877)
- Jeffrey L Goldberg
Glaucoma Research Foundation
- Jeffrey L Goldberg
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal experiments conformed to the ARVO statement for the Use of Animals in Ophthalmic and Vision Research and were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) and the Institutional Biosafety Committee of University of California, San Diego, Scripps Research, and Stanford University.
Copyright
© 2022, Shah et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Quantitative transportomics identifies Kif5a as a major regulator of neurodegeneration
eLife 11:e68148.
https://doi.org/10.7554/eLife.68148
Further reading
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When navigating environments with changing rules, human brain circuits flexibly adapt how and where we retain information to help us achieve our immediate goals.
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When holding visual information temporarily in working memory (WM), the neural representation of the memorandum is distributed across various cortical regions, including visual and frontal cortices. However, the role of stimulus representation in visual and frontal cortices during WM has been controversial. Here, we tested the hypothesis that stimulus representation persists in the frontal cortex to facilitate flexible control demands in WM. During functional MRI, participants flexibly switched between simple WM maintenance of visual stimulus or more complex rule-based categorization of maintained stimulus on a trial-by-trial basis. Our results demonstrated enhanced stimulus representation in the frontal cortex that tracked demands for active WM control and enhanced stimulus representation in the visual cortex that tracked demands for precise WM maintenance. This differential frontal stimulus representation traded off with the newly-generated category representation with varying control demands. Simulation using multi-module recurrent neural networks replicated human neural patterns when stimulus information was preserved for network readout. Altogether, these findings help reconcile the long-standing debate in WM research, and provide empirical and computational evidence that flexible stimulus representation in the frontal cortex during WM serves as a potential neural coding scheme to accommodate the ever-changing environment.
