RanBP9 at the intersection between cofilin and Aβ pathologies: rescue of neurodegenerative changes by RanBP9 reduction

Abstract

Molecular pathways underlying the neurotoxicity and production of amyloid β protein (Aβ) represent potentially promising therapeutic targets for Alzheimer's disease (AD). We recently found that overexpression of the scaffolding protein RanBP9 increases Aβ production in cell lines and in transgenic mice while promoting cofilin activation and mitochondrial dysfunction. Translocation of cofilin to mitochondria and induction of cofilin–actin pathology require the activation/dephosphorylation of cofilin by Slingshot homolog 1 (SSH1) and cysteine oxidation of cofilin. In this study, we found that endogenous RanBP9 positively regulates SSH1 levels and mediates Aβ-induced translocation of cofilin to mitochondria and induction of cofilin–actin pathology in cultured cells, primary neurons, and in vivo. Endogenous level of RanBP9 was also required for Aβ-induced collapse of growth cones in immature neurons (days in vitro 9 (DIV9)) and depletion of synaptic proteins in mature neurons (DIV21). In vivo, amyloid precursor protein (APP)/presenilin-1 (PS1) mice exhibited 3.5-fold increased RanBP9 levels, and RanBP9 reduction protected against cofilin–actin pathology, synaptic damage, gliosis, and Aβ accumulation associated with APP/PS1 mice. Brains slices derived from APP/PS1 mice showed significantly impaired long-term potentiation (LTP), and RanBP9 reduction significantly enhanced paired pulse facilitation and LTP, as well as partially rescued contextual memory deficits associated with APP/PS1 mice. Therefore, these results underscore the critical importance of endogenous RanBP9 not only in Aβ accumulation but also in mediating the neurotoxic actions of Aβ at the level of synaptic plasticity, mitochondria, and cofilin–actin pathology via control of the SSH1-cofilin pathway in vivo.

Actin dynamics and cofilin‐actin rods in alzheimer disease

“…If rod formation does not play a significant role in protecting neurons from apoptotic or necrotic degeneration, they could be an excellent therapeutic target for treatment of AD. Decreasing either cofilin dephosphorylation or total levels of cofilin expression have already proven to be effective in reducing the cognitive deficits in the Aβ‐overproducing mouse [Woo et al, ], so reagents inhibiting slingshot phosphatase or activating LIM kinase would be likely starting points. However, many other approaches, especially those mediating the PrP C and NOX‐dependent pathway, are likely to be fruitful, especially given the broad role of oxidative stress in neurodegeneration.…”

Cellular functions of the ADF/cofilin family at a glance

“…However, cofilin oxidation is dispensable when apoptosis is induced by stimuli other than reactive oxygen species (Klamt et al, 2009) (see poster). Translocation of cofilin to mitochondria also mediates amyloid-β-induced neurotoxicity in a process that involves Ran-binding protein 9 (Woo et al, 2015). In addition to these roles at early stages of apoptosis, cofilin might also be involved in the regulation of apoptosis-associated morphologies during the later stages, such as in apoptosis-associated bleb formation (Mannherz et al, 2005).…”

Peptide regulation of cofilin activity in the CNS: A novel therapeutic approach for treatment of multiple neurological disorders

“…Cofilin phosphoregulation is significantly shifted from the norm in rodent models of many neurological disorders, including AD (Zhao et al, 2006; Woo et al, 2015a; Woo et al, 2015b), autism (Duffney et al, 2015; Liu et al, 2016), manic/bipolar disorder (Lee et al, 2016), sleep deprivation (Havekes et al, 2016), neonatal isolation (Tada et al, 2016), and neuropathic pain (Qiu et al, 2016) (Table 1). Dendritic spine shrinkage occurs as a result of cofilin hyperactivation (dephosphorylation) and has been observed in hippocampal neurons during establishment of long-term depression (Figure 2; Zhou et al, 2004), and in neurons of the hippocampus but not the prefrontal cortex of sleep deprived mice (Havekes et al, 2016).…”

“…Aβ interacts with many synaptic proteins including the cellular prion protein (PrP C ), NMDA receptor, ephrin type B-2 receptor, immunoglobin constant domain gamma receptor IIb, paired immunoglobulin-like receptor B, metabotropic glutamate receptor 5 (mGluR5) and β1-integrin (Benilova and DeStrooper, 2013; Woo et al, 2015b; Um et al, 2013). Many of these synaptic proteins have been linked to effectors modulating cofilin phosphoregulation.…”

“…PrP C is a required co-receptor for binding of Aβ to β1-integrin (Woo et al, 2015a) and mGluR5 (Haas et al, 2016). Furthermore, Aβ-binding to β1-integrin signals in a PrP C -dependent manner through RanBP9, a scaffolding protein and nuclear import factor, leading to cofilin dephosphorylation by SSH (Woo et al, 2015b). In a mouse model of AD (Table 1), decreasing RanBP9 or cofilin expression by crosses with RanBP9 or cofilin hemizygous mice results in protection from learning and memory defects in a contextual fear conditioning response, indicating the importance of cofilin activity levels in hippocampal learning and memory (Woo et al, 2015a; Woo et al, 2015b).…”