| First Author | Woo JA | Year | 2012 |
| Journal | Cell Death Differ | Volume | 19 |
| Issue | 9 | Pages | 1413-23 |
| PubMed ID | 22361682 | Mgi Jnum | J:204630 |
| Mgi Id | MGI:5532902 | Doi | 10.1038/cdd.2012.14 |
| Citation | Woo JA, et al. (2012) Pivotal role of the RanBP9-cofilin pathway in Abeta-induced apoptosis and neurodegeneration. Cell Death Differ 19(9):1413-23 |
| abstractText | Neurodegeneration associated with amyloid beta (Abeta) peptide accumulation, synaptic loss, neuroinflammation, tauopathy, and memory impairments encompass the pathophysiological features of Alzheimer's disease (AD). We previously reported that the scaffolding protein RanBP9, which is overall increased in brains of AD patients, simultaneously promotes Abeta generation and focal adhesion disruption by accelerating the endocytosis of amyloid precursor protein (APP) and beta1-integrin, respectively. Here, we show that RanBP9 protein levels are increased by fourfold in FAD mutant APP transgenic mice. Accordingly, RanBP9 transgenic mice demonstrate significantly increased synapse loss, neurodegeneration, gliosis, and spatial memory deficits. RanBP9 overexpression promotes apoptosis and potentiates Abeta-induced neurotoxicity independent of its capacity to promote Abeta generation. Conversely, RanBP9 reduction by siRNA or gene dosage mitigates Abeta-induced neurotoxicity. Importantly, RanBP9 activates/dephosphorylates cofilin, a key regulator of actin dynamics and mitochondria-mediated apoptosis, and siRNA knockdown of cofilin abolishes both Abeta and RanBP9-induced apoptosis. These findings implicate the RanBP9-cofilin pathway as critical therapeutic targets not only for stemming Abeta generation but also antagonizing Abeta-induced neurotoxicity. |
