Latrepirdine stimulates autophagy and reduces accumulation of α-synuclein in cells and in mouse brain (original) (raw)

Molecular Psychiatry volume 18, pages 882–888 (2013)Cite this article

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Abstract

Latrepirdine (Dimebon; dimebolin) is a neuroactive compound that was associated with enhanced cognition, neuroprotection and neurogenesis in laboratory animals, and has entered phase II clinical trials for both Alzheimer's disease and Huntington's disease (HD). Based on recent indications that latrepirdine protects cells against cytotoxicity associated with expression of aggregatable neurodegeneration-related proteins, including Aβ42 and γ-synuclein, we sought to determine whether latrepirdine offers protection to Saccharomyces cerevisiae. We utilized separate and parallel expression in yeast of several neurodegeneration-related proteins, including α-synuclein (α-syn), the amyotrophic lateral sclerosis-associated genes TDP43 and FUS, and the HD-associated protein huntingtin with a 103 copy-polyglutamine expansion (HTT gene; htt-103Q). Latrepirdine effects on α-syn clearance and toxicity were also measured following treatment of SH-SY5Y cells or chronic treatment of wild-type mice. Latrepirdine only protected yeast against the cytotoxicity associated with α-syn, and this appeared to occur via induction of autophagy. We further report that latrepirdine stimulated the degradation of α-syn in differentiated SH-SY5Y neurons, and in mouse brain following chronic administration, in parallel with elevation of the levels of markers of autophagic activity. Ongoing experiments will determine the utility of latrepirdine to abrogate α-syn accumulation in transgenic mouse models of α-syn neuropathology. We propose that latrepirdine may represent a novel scaffold for discovery of robust pro-autophagic/anti-neurodegeneration compounds, which might yield clinical benefit for synucleinopathies including Parkinson's disease, Lewy body dementia, rapid eye movement (REM) sleep disorder and/or multiple system atrophy, following optimization of its pro-autophagic and pro-neurogenic activities.

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Acknowledgements

The work in this manuscript was used in a dissertation by JWS as partial requirement for the fulfillment of the PhD degree. JWS is a trainee in the Integrated Pharmacological Sciences Training Program supported by grant T32GM062754 from the National Institute of General Medical Sciences. MLL was supported by the Deutsche Forschungsgemeinschaft. SG is a member of the Oligomer Research Consortium of the Cure Alzheimer's Fund. We acknowledge the generous support of the NH&MRC (APP1009295 to RM, GV, SG), McCusker Alzheimer's Research Foundation (RM, GV), Conicyt (PFB-16 to SB), Fidelity Biosciences Research Initiative (SJ, JL, DR, GAP), Cure Alzheimer's Fund (SG), the US Department of Veterans Affairs (SG), and the NIH (P01AG10491 to SG; P50AG05138 to Mary Sano; P30 NS061777 and S10 RR022415 to RW; R01NS060123 and U54RR022220 to ZY). We would like to thank Rosilyn Kazanjian for her gift in memory of Powel Kazanjian. We would also like to thank Loren E Khan and Justine Bonet for technical assistance in animal colony management and Dr Yun Zhong for technical support, and Dr Kostas Vekrellis (Foundation for Biomedical Research of the Academy of Athens, Athens, Greece) for generously providing the tet-off inducible α-syn overexpressing SH-SY5Y neuroblastoma cell line.

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Author notes

  1. J W Steele, S Ju and M L Lachenmayer: These authors contributed equally.

Authors and Affiliations

  1. Department of Neurology, Mount Sinai School of Medicine, New York, NY, USA
    J W Steele, M L Lachenmayer, A Stock, S H Kim, M E Ehrlich, Z Yue & S Gandy
  2. Department of Psychiatry and Mount Sinai Alzheimer's Disease Research Center, Mount Sinai School of Medicine, New York, NY, USA
    J W Steele, A Stock, S H Kim & S Gandy
  3. Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, New York, NY, USA
    J W Steele
  4. Departments of Biochemistry and Chemistry, Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, MA, USA
    S Ju, J Liken, D Ringe & G A Petsko
  5. Department of Neurology, University of Bonn, Bonn, Germany
    M L Lachenmayer
  6. Facultad de Ciencias Biológicas, Universidad Andrés Bello, Santiago, Chile
    L M Delgado
  7. Fundación Ciencia & Vida, Santiago, Chile
    I E Alfaro & S Bernales
  8. Medivation, Inc., San Francisco, CA, USA
    S Bernales & A A Protter
  9. Centre of Excellence for Alzheimer's Disease Research and Care, School of Medical Sciences, Edith Cowan University, Western Australia, Australia
    G Verdile, P Bharadwaj, V Gupta, R Barr & R N Martins
  10. Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY, USA
    A Friss, G Dolios, R Wang & M E Ehrlich
  11. School of Psychiatry and Clinical Neurosciences, University of Western Australia, Crawley, Western Australia, Australia
    R N Martins
  12. Sir James McCusker Alzheimer's Disease Research Unit, Hollywood Private Hospital, Nedlands, Western Australia, Australia
    R N Martins
  13. Department of Pediatrics, Mount Sinai School of Medicine, New York, NY, USA
    M E Ehrlich
  14. Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, USA
    Z Yue
  15. Department of Neurology and Neurosciences, Weill Medical College of Cornell University, New York, NY, USA
    G A Petsko
  16. James J Peters VA Medical Center, Bronx, NY, USA
    S Gandy

Authors

  1. J W Steele
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  2. S Ju
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  3. M L Lachenmayer
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  4. J Liken
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  5. A Stock
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  6. S H Kim
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  7. L M Delgado
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  8. I E Alfaro
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  9. S Bernales
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  10. G Verdile
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  11. P Bharadwaj
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  12. V Gupta
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  13. R Barr
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  14. A Friss
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  15. G Dolios
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  16. R Wang
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  17. D Ringe
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  18. A A Protter
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  19. R N Martins
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  20. M E Ehrlich
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  21. Z Yue
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  22. G A Petsko
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  23. S Gandy
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Corresponding author

Correspondence toS Gandy.

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Competing interests

AAP is Vice President of Preclinical Development for Medivation. SG holds research grant support from Amicus Pharmaceuticals and is a consultant to the Pfizer-Janssen Alzheimer's Immunotherapy Alliance. GAP is on the scientific advisory boards of Amicus Pharmaceuticals and Neurophage. The remaining authors declare no conflict of interest.

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Steele, J., Ju, S., Lachenmayer, M. et al. Latrepirdine stimulates autophagy and reduces accumulation of α-synuclein in cells and in mouse brain.Mol Psychiatry 18, 882–888 (2013). https://doi.org/10.1038/mp.2012.115

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