Small molecule modulator of neuronal lysosome positioning and function resolves Alzheimer’s Disease-linked pathologies in cultured human neurons

  1. Amanda M. Snead
  2. Sruchi Patel
  3. Mia Krout
  4. Ryan S. Hippman
  5. Gabrielle Smith
  6. Diya Dileep
  7. Nitya Chagoor
  8. Rachel Shi
  9. Ricardo Linares
  10. Andrew Dobria
  11. Stephanie M. Cologna
  12. Camerron Crowder
  13. Leslie N. Aldrich
  14. Swetha Gowrishankar

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Abstract

Abnormal increase in axonal lysosome abundance is associated with multiple neurodegenerative diseases including Alzheimer’s disease. However, the underlying mechanisms and disease relevance are not fully understood. We have recently identified RH1115 as a small molecule modulator of the autophagy-lysosomal pathway that regulates lysosome positioning in neurons. This allowed us to manipulate neuronal lysosome distribution including in axons and interrogate its contribution to both optimal neuronal functioning and to disease pathology. We demonstrate that the small molecule not only rescues aberrant buildup of both axonal autophagic and lysosomal intermediates but also reduces secreted Aβ42 levels in human iPSC-derived neurons lacking the lysosomal adaptor, JIP3. We thus demonstrate that restoring efficient axonal lysosome transport has an anti-amyloidogenic effect in human neurons and is a promising therapeutic strategy for Alzheimer’s disease. Furthermore, we show that the small molecule enhances neuronal lysosome degradation, requires the lysosomal adaptor JIP4 to rescue the axonal lysosome pathology in the JIP3 KO neurons and increases levels of the JIP4-interacting lysosomal membrane protein, TMEM55B. Lastly, treatment with the small molecule led to a striking rescue of locomotor defects in JIP3 KO zebrafish larvae. Thus, we have identified a small molecule which can be impactful in neurodegenerative diseases that have a lysosomal pathology and have determined its molecular targets in modulating axonal lysosome abundance.

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  1. PREreview

    This Zenodo record is a permanently preserved version of a Structured PREreview. You can view the complete PREreview at https://prereview.org/reviews/14721167.

    Does the introduction explain the objective of the research presented in the preprint? Yes
    Are the methods well-suited for this research? Somewhat appropriate
    Are the conclusions supported by the data? Highly supported
    Are the data presentations, including visualizations, well-suited to represent the data? Somewhat appropriate and clear
    How clearly do the authors discuss, explain, and interpret their findings and potential next steps for the research? Very clearly
    Is the preprint likely to advance academic knowledge? Highly likely
    Would it benefit from language editing? No
    Would you recommend this preprint to others? Yes, but it needs to be improved
    Is it ready for attention from an editor, publisher or broader audience? Yes, after minor changes

    Competing interests

    The authors declare that they have no competing interests.

  2. Version published to 10.1101/2024.11.04.621986 on bioRxiv