A fragment of the scaffolding protein RanBP9 is increased in Alzheimer's disease brains and strongly potentiates amyloid‐β peptide generation

Lakshmana, Madepalli K.; Chung, John Y. L.; Wickramarachchi, Supul; Tak, Eileen; Bianchi, Elisabetta; Koo, Edward H.; Kang, David E.

doi:10.1096/fj.09-136457

Cited by 56 publications

(77 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Together with our previous demonstration that RanBP9 robustly enhances Ab generation, [6][7][8] these data further implicate the RanBP9-cofilin pathway not only as therapeutic targets to stem Ab generation but also block the neurotoxic effects of Ab.…”

Section: Discussionsupporting

confidence: 73%

“…We previously demonstrated that the overall levels RanBP9, particularly the bioactive N-terminal 60 kD fragment (N60), is increased in brains of AD patients compared with the age-matched healthy controls. 8 Thus, we assessed whether RanBP9 levels might be altered in a mouse model of AD pathology. In brains of 10-12-month-old J20 APP transgenic mice carrying both the Swedish and Indiana APP mutations, RanBP9 levels were increased by more than fourfold in J20 mice compared with their non-transgenic counterparts (Figures 1a and b).…”

Section: Resultsmentioning

confidence: 99%

“…Plasmids pLHCX Flag-RanBP9, p3X Flag-RanBP9, pEGFP-RanBP9, and pEYFP-N1 constructs have previously been described. 6,8 To examine the stage of apoptotic cells, the measurements were carried out using FACS Calibur (BD Bioscience, San Jose, CA, USA) or fluorescence microscopy. Cells were either trypsinized/collected stained in solution or directly on glass coverslips with Annexin V-fluorescein and PI for 20 min at 25 1C in the dark state using the FITC Annexin V apoptosis detection kit I (BD, San Diego, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

“…6 In addition, a 60-kD proteolytic fragment of RanBP9 is increased by more than sixfold in brains of AD patients, and this fragment potentiates Ab generation via BACE1 processing of APP. 8 In addition to promoting Ab generation by accelerating APP endocytosis, RanBP9 also potently disrupts integrin-dependent focal adhesion signaling and assembly by accelerating b1-integrin and LRP endocytosis. 9 In this study, we found that RanBP9 levels are increased not only in brains of AD patients but also in APP transgenic mice.…”

mentioning

confidence: 99%

See 3 more Smart Citations

Pivotal role of the RanBP9-cofilin pathway in Aβ-induced apoptosis and neurodegeneration

et al. 2012

View full text Add to dashboard Cite

Neurodegeneration associated with amyloid b (Ab) 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 Ab generation and focal adhesion disruption by accelerating the endocytosis of amyloid precursor protein (APP) and b1-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 Ab-induced neurotoxicity independent of its capacity to promote Ab generation. Conversely, RanBP9 reduction by siRNA or gene dosage mitigates Ab-induced neurotoxicity. Importantly, RanBP9 activates/dephosphorylates cofilin, a key regulator of actin dynamics and mitochondria-mediated apoptosis, and siRNA knockdown of cofilin abolishes both Ab and RanBP9-induced apoptosis. These findings implicate the RanBP9-cofilin pathway as critical therapeutic targets not only for stemming Ab generation but also antagonizing Ab-induced neurotoxicity. Cell Death and Differentiation (2012) 19, 1413-1423; doi:10.1038/cdd.2012.14; published online 24 February 2012Alzheimer's disease (AD) is a neurodegenerative disorder characterized by accumulations of the amyloid b (Ab) -peptide and hyperphosphorylated tau in senile plaques and neurofibrillary tangles, respectively. Ab is a neurotoxic peptide derived from b-and g-secretase cleavages of the amyloid precursor protein (APP) and is thought to be a critical early player in AD pathogenesis. 1 In addition to the accumulation of Ab and tau, abnormalities in the actin cytoskeleton are detected earlier during the course of AD and other neurodegenerative diseases. 2 Indeed, it has been demonstrated that Ab can induce actin/cofilin pathology associated with hyperphosphorylated tau in primary neurons and in vivo. [3][4][5] We recently demonstrated that the scaffolding protein RanBP9 interacts with the cytoplasmic tails of LRP, APP, and BACE1, and functions as a scaffold upon which APP is brought together with BACE1 and LRP. Such interactions of RanBP9 promote the endocytosis of APP and strongly increase BACE1 cleavage of APP to generate Ab in vitro and in vivo. 6,7 Conversely, siRNA knockdown of RanBP9 reduces BACE1 cleavage of APP and Ab generation, indicating that endogenous RanBP9 normally functions in this capacity. 6 In addition, a 60-kD proteolytic fragment of RanBP9 is increased by more than sixfold in brains of AD patients, and this fragment potentiates Ab generation via BACE1 processing of APP. 8 In addition to promoting Ab generation by accelerating APP endocytosis, RanBP9 also potently disrupts integrin-dependent focal adhesion signaling and assembly by accelerating b1-integrin and LRP endocytosis. 9 In th...

show abstract

Section: Discussionsupporting

confidence: 73%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Pivotal role of the RanBP9-cofilin pathway in Aβ-induced apoptosis and neurodegeneration

et al. 2012

View full text Add to dashboard Cite

show abstract

“…Recently, RanBP9 was found to be within the clusters of RNA transcript pairs associated with markers of AD progression, suggesting that RanBP9 might contribute to the pathogenesis of AD (9). In fact, even before this finding, we showed for the first time that RanBP9 protein levels are increased 6-fold in AD brains (10) and that RanBP9 overexpression increases A␤ generation 4-fold in cell cultures by increasing ␤-secretase-mediated processing of APP (11) and also increases amyloid plaques in mouse brains (12), which, in turn, leads to a significant loss of synaptic proteins (12). Because RanBP9 is known to exist in large multiprotein complexes of greater than 670 kDa (13,14), we speculated that A␤ generation may be modulated by several other RanBP9-binding proteins.…”

Section: Alzheimer's Disease (Ad)mentioning

confidence: 52%

COPS5 (Jab1) Protein Increases β Site Processing of Amyloid Precursor Protein and Amyloid β Peptide Generation by Stabilizing RanBP9 Protein Levels

Wang

Dey

Carrera

et al. 2013

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Background: Increased generation of toxic amyloid ␤ peptide (A␤) in the brain is central to the pathogenesis of Alzheimer's disease (AD). Results: COPS5 (Jab1) is a novel RanBP9-interacting protein that robustly increases A␤ generation Conclusion: COPS5 increases A␤ generation by stabilizing RanBP9 protein levels. Significance: Lowering COPS5 levels may be an effective therapeutic approach for AD.

show abstract

Neuromechanobiology: An Expanding Field Driven by the Force of Greater Focus

Motz

Kabat

Saxena

et al. 2021

Adv Healthcare Materials

View full text Add to dashboard Cite

The brain processes information by transmitting signals through highly connected and dynamic networks of neurons. Neurons use specific cellular structures, including axons, dendrites and synapses, and specific molecules, including cell adhesion molecules, ion channels and chemical receptors to form, maintain and communicate among cells in the networks. These cellular and molecular processes take place in environments rich of mechanical cues, thus offering ample opportunities for mechanical regulation of neural development and function. Recent studies have suggested the importance of mechanical cues and their potential regulatory roles in the development and maintenance of these neuronal structures. Also suggested are the importance of mechanical cues and their potential regulatory roles in the interaction and function of molecules mediating the interneuronal communications. In this review, the current understanding is integrated and promising future directions of neuromechanobiology are suggested at the cellular and molecular levels. Several neuronal processes where mechanics likely plays a role are examined and how forces affect ligand binding, conformational change, and signal induction of molecules key to these neuronal processes are indicated, especially at the synapse. The disease relevance of neuromechanobiology as well as therapies and engineering solutions to neurological disorders stemmed from this emergent field of study are also discussed.

show abstract

A fragment of the scaffolding protein RanBP9 is increased in Alzheimer's disease brains and strongly potentiates amyloid‐β peptide generation

Cited by 56 publications

References 33 publications

Pivotal role of the RanBP9-cofilin pathway in Aβ-induced apoptosis and neurodegeneration

Pivotal role of the RanBP9-cofilin pathway in Aβ-induced apoptosis and neurodegeneration

COPS5 (Jab1) Protein Increases β Site Processing of Amyloid Precursor Protein and Amyloid β Peptide Generation by Stabilizing RanBP9 Protein Levels

Neuromechanobiology: An Expanding Field Driven by the Force of Greater Focus

Contact Info

Product

Resources

About