| First Author | Larson ME | Year | 2017 |
| Journal | Proc Natl Acad Sci U S A | Volume | 114 |
| Issue | 23 | Pages | E4648-E4657 |
| PubMed ID | 28533388 | Mgi Jnum | J:242277 |
| Mgi Id | MGI:5904869 | Doi | 10.1073/pnas.1704698114 |
| Citation | Larson ME, et al. (2017) Selective lowering of synapsins induced by oligomeric alpha-synuclein exacerbates memory deficits. Proc Natl Acad Sci U S A 114(23):E4648-E4657 |
| abstractText | Mounting evidence indicates that soluble oligomeric forms of amyloid proteins linked to neurodegenerative disorders, such as amyloid-beta (Abeta), tau, or alpha-synuclein (alphaSyn) might be the major deleterious species for neuronal function in these diseases. Here, we found an abnormal accumulation of oligomeric alphaSyn species in AD brains by custom ELISA, size-exclusion chromatography, and nondenaturing/denaturing immunoblotting techniques. Importantly, the abundance of alphaSyn oligomers in human brain tissue correlated with cognitive impairment and reductions in synapsin expression. By overexpressing WT human alphaSyn in an AD mouse model, we artificially enhanced alphaSyn oligomerization. These bigenic mice displayed exacerbated Abeta-induced cognitive deficits and a selective decrease in synapsins. Following isolation of various soluble alphaSyn assemblies from transgenic mice, we found that in vitro delivery of exogenous oligomeric alphaSyn but not monomeric alphaSyn was causing a lowering in synapsin-I/II protein abundance. For a particular alphaSyn oligomer, these changes were either dependent or independent on endogenous alphaSyn expression. Finally, at a molecular level, the expression of synapsin genes SYN1 and SYN2 was down-regulated in vivo and in vitro by alphaSyn oligomers, which decreased two transcription factors, cAMP response element binding and Nurr1, controlling synapsin gene promoter activity. Overall, our results demonstrate that endogenous alphaSyn oligomers can impair memory by selectively lowering synapsin expression. |
