Synthesis and Characterization of Click Chemical Probes for Single-Cell Resolution Detection of Epichaperomes in Neurodegenerative Disorders

  • Biomedicines. 2024 Jun 4;12(6):1252. doi: 10.3390/biomedicines12061252.
Sadik Bay  1 ,  Chander S Digwal  1 ,  Ananda M Rodilla Martín  1 ,  Sahil Sharma  1 ,  Aleksandra Stanisavljevic  2 ,  Anna Rodina  1 ,  Anoosha Attaran  3  4 ,  Tanaya Roychowdhury  1 ,  Kamya Parikh  1 ,  Eugene Toth  1 ,  Palak Panchal  1 ,  Eric Rosiek  5 ,  Chiranjeevi Pasala  1 ,  Ottavio Arancio  6  7  8 ,  Paul E Fraser  9 ,  Melissa J Alldred  2  10 ,  Marco A M Prado  3  4 ,  Stephen D Ginsberg  2  10  11 ,  Gabriela Chiosis  1  12
Affiliations
  • 1. Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 2. Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY 10962, USA.
  • 3. Department of Physiology and Pharmacology, Schulich School of Medicine, Robarts Research Institute, The University of Western Ontario, London, ON N6A 3K7, Canada.
  • 4. Department of Anatomy and Cell Biology, Schulich School of Medicine, Robarts Research Institute, The University of Western Ontario, London, ON N6A 3K7, Canada.
  • 5. Molecular Cytology Core, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 6. Taub Institute for Research on Alzheimer's Disease and the Aging Brain, New York, NY 10032, USA.
  • 7. Department of Medicine, Columbia University, New York, NY 10032, USA.
  • 8. Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA.
  • 9. Tanz Centre for Research in Neurodegenerative Diseases and Department of Medical Biophysics, University of Toronto, Toronto, ON M5R 0A3, Canada.
  • 10. Departments of Psychiatry, NYU Grossman School of Medicine, New York, NY 10016, USA.
  • 11. Neuroscience & Physiology & the NYU Neuroscience Institute, NYU Grossman School of Medicine, New York, NY 10016, USA.
  • 12. Department of Medicine, Division of Solid Tumors, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
PMID: 38927459 DOI: 10.3390/biomedicines12061252
Abstract

Neurodegenerative disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD), represent debilitating conditions with complex, poorly understood pathologies. Epichaperomes, pathologic protein assemblies nucleated on key chaperones, have emerged as critical players in the molecular dysfunction underlying these disorders. In this study, we introduce the synthesis and characterization of clickable epichaperome probes, PU-TCO, positive control, and PU-NTCO, negative control. Through comprehensive in vitro assays and cell-based investigations, we establish the specificity of the PU-TCO probe for epichaperomes. Furthermore, we demonstrate the efficacy of PU-TCO in detecting epichaperomes in brain tissue with a cellular resolution, underscoring its potential as a valuable tool for dissecting single-cell responses in neurodegenerative diseases. This clickable probe is therefore poised to address a critical need in the field, offering unprecedented precision and versatility in studying epichaperomes and opening avenues for novel insights into their role in disease pathology.

Keywords
click probes; drug discovery; epichaperomes; fluorescence imaging; imaging probe; neurodegenerative disease; therapeutic strategy.
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