Dataset Information

Pivotal role of the RanBP9-cofilin pathway in A?-induced apoptosis and neurodegeneration.

ABSTRACT: Neurodegeneration associated with amyloid ? (A?) 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 A? generation and focal adhesion disruption by accelerating the endocytosis of amyloid precursor protein (APP) and ?1-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 A?-induced neurotoxicity independent of its capacity to promote A? generation. Conversely, RanBP9 reduction by siRNA or gene dosage mitigates A?-induced neurotoxicity. Importantly, RanBP9 activates/dephosphorylates cofilin, a key regulator of actin dynamics and mitochondria-mediated apoptosis, and siRNA knockdown of cofilin abolishes both A? and RanBP9-induced apoptosis. These findings implicate the RanBP9-cofilin pathway as critical therapeutic targets not only for stemming A? generation but also antagonizing A?-induced neurotoxicity.

SUBMITTER: Woo JA

PROVIDER: S-EPMC3422466 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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

Woo J A JA Jung A R AR Lakshmana M K MK Bedrossian A A Lim Y Y Bu J H JH Park S A SA Koo E H EH Mook-Jung I I Kang D E DE

Cell death and differentiation 20120224 9

Neurodegeneration associated with amyloid β (Aβ) 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 Aβ generation and focal adhesion disruption by accelerating the endocytosis of amyloid precursor protein (APP) and β1-integrin, respectively. Here, we sh ...[more]

PMID: 22361682

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Project description:This comprehensive review explores the complex role of cofilin, an actin-binding protein, across various neurodegenerative diseases (Alzheimer's, Parkinson's, schizophrenia, amyotrophic lateral sclerosis (ALS), Huntington's) and stroke. Cofilin is an essential protein in cytoskeletal dynamics, and any dysregulation could lead to potentially serious complications. Cofilin's involvement is underscored by its impact on pathological hallmarks like Aβ plaques and α-synuclein aggregates, triggering synaptic dysfunction, dendritic spine loss, and impaired neuronal plasticity, leading to cognitive decline. In Parkinson's disease, cofilin collaborates with α-synuclein, exacerbating neurotoxicity and impairing mitochondrial and axonal function. ALS and frontotemporal dementia showcase cofilin's association with genetic factors like C9ORF72, affecting actin dynamics and contributing to neurotoxicity. Huntington's disease brings cofilin into focus by impairing microglial migration and influencing synaptic plasticity through AMPA receptor regulation. Alzheimer's, Parkinson's, and schizophrenia exhibit 14-3-3 proteins in cofilin dysregulation as a shared pathological mechanism. In the case of stroke, cofilin takes center stage, mediating neurotoxicity and neuronal cell death. Notably, there is a potential overlap in the pathologies and involvement of cofilin in various diseases. In this context, referencing cofilin dysfunction could provide valuable insights into the common pathologies associated with the aforementioned conditions. Moreover, this review explores promising therapeutic interventions, including cofilin inhibitors and gene therapy, demonstrating efficacy in preclinical models. Challenges in inhibitor development, brain delivery, tissue/cell specificity, and long-term safety are acknowledged, emphasizing the need for precision drug therapy. The call to action involves collaborative research, biomarker identification, and advancing translational efforts. Cofilin emerges as a pivotal player, offering potential as a therapeutic target. However, unraveling its complexities requires concerted multidisciplinary efforts for nuanced and effective interventions across the intricate landscape of neurodegenerative diseases and stroke, presenting a hopeful avenue for improved patient care.

Dataset Information

Pivotal role of the RanBP9-cofilin pathway in A?-induced apoptosis and neurodegeneration.

Publications

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

Similar Datasets

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