Exploring therapeutic strategies for infantile neuronal axonal dystrophy (INAD/PARK14)

  1. Guang Lin
  2. Burak Tepe
  3. Geoff McGrane
  4. Regine C Tipon
  5. Gist Croft
  6. Leena Panwala
  7. Amanda Hope
  8. Agnes JH Liang
  9. Zhongyuan Zuo
  10. Seul Kee Byeon
  11. Lily Wang
  12. Akhilesh Pandey
  13. Hugo J Bellen  Is a corresponding author
  1. Baylor College of Medicine, United States
  2. New York Stem Cell Foundation, United States
  3. INADcure Foundation, United States
  4. Mayo Clinic, United States

Abstract

Infantile Neuroaxonal Dystrophy (INAD) is caused by recessive variants in PLA2G6 and is a lethal pediatric neurodegenerative disorder. Loss of the Drosophila homolog of PLA2G6, leads to ceramide accumulation, lysosome expansion, and mitochondrial defects. Here, we report that retromer function, ceramide metabolism, the endolysosomal pathway, and mitochondrial morphology are affected in INAD patient-derived neurons. We show that in INAD mouse models the same features are affected in Purkinje cells, arguing that the neuropathological mechanisms are evolutionary conserved and that these features can be used as biomarkers. We tested 20 drugs that target these pathways and found that Ambroxol, Desipramine, Azoramide, and Genistein alleviate neurodegenerative phenotypes in INAD flies and INAD patient-derived NPCs. We also develop an AAV-based gene therapy approach that delays neurodegeneration and prolongs lifespan in an INAD mouse model.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting file; Source Data files have been provided for Figures 1, 3, 4 and Suppl. Figure 1.

Article and author information

Author details

  1. Guang Lin

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5594-3397
  2. Burak Tepe

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4371-2502
  3. Geoff McGrane

    New York Stem Cell Foundation, New York, United States
    Competing interests
    No competing interests declared.
  4. Regine C Tipon

    New York Stem Cell Foundation, New York, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5473-7353
  5. Gist Croft

    New York Stem Cell Foundation, New York, United States
    Competing interests
    No competing interests declared.
  6. Leena Panwala

    INADcure Foundation, New Jersey, United States
    Competing interests
    No competing interests declared.
  7. Amanda Hope

    INADcure Foundation, New Jersey, United States
    Competing interests
    No competing interests declared.
  8. Agnes JH Liang

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  9. Zhongyuan Zuo

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  10. Seul Kee Byeon

    Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, United States
    Competing interests
    No competing interests declared.
  11. Lily Wang

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  12. Akhilesh Pandey

    Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9943-6127
  13. Hugo J Bellen

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    For correspondence
    hbellen@bcm.edu
    Competing interests
    Hugo J Bellen, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5992-5989

Funding

Baylor College of Medicine (P50HD103555)

  • Hugo J Bellen

Huffington Foundation

  • Hugo J Bellen

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 experimental animals were treated in compliance with the United States Department of Health and Human Services and the Baylor College of Medicine IACUC guidelines. Protocol (AN-5596).

Reviewing Editor

  1. Suzanne R Pfeffer, Stanford University, United States

Publication history

  1. Received: August 9, 2022
  2. Accepted: January 15, 2023
  3. Accepted Manuscript published: January 16, 2023 (version 1)

Copyright

© 2023, Lin 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.

Metrics

  • 397
    Page views
  • 109
    Downloads
  • 0
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Guang Lin
  2. Burak Tepe
  3. Geoff McGrane
  4. Regine C Tipon
  5. Gist Croft
  6. Leena Panwala
  7. Amanda Hope
  8. Agnes JH Liang
  9. Zhongyuan Zuo
  10. Seul Kee Byeon
  11. Lily Wang
  12. Akhilesh Pandey
  13. Hugo J Bellen
(2023)
Exploring therapeutic strategies for infantile neuronal axonal dystrophy (INAD/PARK14)
eLife 12:e82555.
https://doi.org/10.7554/eLife.82555

Further reading

    1. Neuroscience
    2. Physics of Living Systems
    Sabrina A Jones, Jacob H Barfield ... Woodrow L Shew
    Research Article

    Naturally occurring body movements and collective neural activity both exhibit complex dynamics, often with scale-free, fractal spatiotemporal structure. Scale-free dynamics of both brain and behavior are important because each is associated with functional benefits to the organism. Despite their similarities, scale-free brain activity and scale-free behavior have been studied separately, without a unified explanation. Here we show that scale-free dynamics of mouse behavior and neurons in visual cortex are strongly related. Surprisingly, the scale-free neural activity is limited to specific subsets of neurons, and these scale-free subsets exhibit stochastic winner-take-all competition with other neural subsets. This observation is inconsistent with prevailing theories of scale-free dynamics in neural systems, which stem from the criticality hypothesis. We develop a computational model which incorporates known cell-type-specific circuit structure, explaining our findings with a new type of critical dynamics. Our results establish neural underpinnings of scale-free behavior and clear behavioral relevance of scale-free neural activity.

    1. Neuroscience
    Barna Zajzon, David Dahmen ... Renato Duarte
    Research Article

    Information from the sensory periphery is conveyed to the cortex via structured projection pathways that spatially segregate stimulus features, providing a robust and efficient encoding strategy. Beyond sensory encoding, this prominent anatomical feature extends throughout the neocortex. However, the extent to which it influences cortical processing is unclear. In this study, we combine cortical circuit modeling with network theory to demonstrate that the sharpness of topographic projections acts as a bifurcation parameter, controlling the macroscopic dynamics and representational precision across a modular network. By shifting the balance of excitation and inhibition, topographic modularity gradually increases task performance and improves the signal-to-noise ratio across the system. We demonstrate that in biologically constrained networks, such a denoising behavior is contingent on recurrent inhibition. We show that this is a robust and generic structural feature that enables a broad range of behaviorally-relevant operating regimes, and provide an in-depth theoretical analysis unravelling the dynamical principles underlying the mechanism.