Selective lowering of synapsins induced by oligomeric α-synuclein exacerbates memory deficits

Megan E. Larson, Susan J. Greimel, Fatou Amar, Michael LaCroix, Gabriel Boyle, Mathew A. Sherman, Hallie Schley, Camille Miel, Julie A. Schneider, Rakez Kayed, Fabio Benfenati, Michael K. Lee, David A. Bennett, Sylvain E. Lesné

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

Mounting evidence indicates that soluble oligomeric forms of amyloid proteins linked to neurodegenerative disorders, such as amyloid-β (Aβ), tau, or α-synuclein (aSyn) might be the major deleterious species for neuronal function in these diseases. Here, we found an abnormal accumulation of oligomeric aSyn species in AD brains by custom ELISA, size-exclusion chromatography, and nondenaturing/denaturing immunoblotting techniques. Importantly, the abundance of aSyn oligomers in human brain tissue correlated with cognitive impairment and reductions in synapsin expression. By overexpressing WT human aSyn in an AD mouse model, we artificially enhanced aSyn oligomerization. These bigenic mice displayed exacerbated Aβ-induced cognitive deficits and a selective decrease in synapsins. Following isolation of various soluble aSyn assemblies from transgenic mice, we found that in vitro delivery of exogenous oligomeric aSyn but not monomeric aSyn was causing a lowering in synapsin-I/II protein abundance. For a particular aSyn oligomer, these changes were either dependent or independent on endogenous aSyn expression. Finally, at a molecular level, the expression of synapsin genes SYN1 and SYN2 was down-regulated in vivo and in vitro by aSyn oligomers, which decreased two transcription factors, cAMP response element binding and Nurr1, controlling synapsin gene promoter activity. Overall, our results demonstrate that endogenous aSyn oligomers can impair memory by selectively lowering synapsin expression.

Original languageEnglish (US)
Pages (from-to)E4648-E4657
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number23
DOIs
StatePublished - Jun 6 2017

Keywords

  • Alzheimer's disease
  • Memory
  • Oligomer
  • Synapsins
  • α-synuclein

ASJC Scopus subject areas

  • General

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    Larson, M. E., Greimel, S. J., Amar, F., LaCroix, M., Boyle, G., Sherman, M. A., Schley, H., Miel, C., Schneider, J. A., Kayed, R., Benfenati, F., Lee, M. K., Bennett, D. A., & Lesné, S. E. (2017). Selective lowering of synapsins induced by oligomeric α-synuclein exacerbates memory deficits. Proceedings of the National Academy of Sciences of the United States of America, 114(23), E4648-E4657. https://doi.org/10.1073/pnas.1704698114