H. Salapa

University of Saskatchewan Medicine

Author Of 1 Presentation

Pathogenesis – Neurodegeneration Oral Presentation

YI01.03 - Inhibition of neuronal RNA binding protein dysfunction as a treatment for neurodegeneration in multiple sclerosis

Speakers
Presentation Number
YI01.03
Presentation Topic
Pathogenesis – Neurodegeneration
Lecture Time
11:24 - 11:36

Abstract

Background

Dysfunctional RNA binding proteins (RBPs), including heterogeneous nuclear ribonucleoprotein A1 (A1), are key pathological features of numerous neurologic diseases. Recently, evidence suggests that dysfunctional RBP biology, including mislocalization of the RBP from its homeostatic nuclear location to the cytoplasm, stress granule (SG) formation, and changes in RNA metabolism, are associated with neurodegeneration and worsened disease in multiple sclerosis (MS) and its models, such as experimental autoimmune encephalomyelitis (EAE).

Objectives

We hypothesized that correcting dysfunctional RBP biology with the nuclear export inhibitor, KPT-276, would restore A1 function by decreasing its nucleocytoplasmic mislocalization and reduce SG formation and neurodegeneration in spinal cord neurons from EAE animals as compared to vehicle controls.

Methods

C57BL/6 female mice were immunized with myelin oligodendrocyte glycoprotein (MOG35-55) to induce EAE. Upon reaching a clinical score of 2.5, mice were treated with KPT-276 (75 mg/kg, oral gavage) or vehicle control every other day for a total of six treatments. Two days following the final treatment, spinal cords were harvested and analyzed using immunofluorescence for A1 localization and SG formation in neurons as well as markers of neurodegeneration.

Results

EAE mice treated with KPT-276 showed a decrease in clinical score severity as compared to vehicle control EAE mice. Furthermore, mice treated with KPT-276 showed a significant reduction in the number of neurons with A1 mislocalization (*p=0.0351), the amount of A1 in the cytoplasm (*p=0.0341), and SG formation (*p=0.0208) as compared to vehicle mice. In the same areas of KPT-276 treated mice where there was a reduction in these features of dysfunctional RBP biology, there was a significant increase in the number of neurons indicative of increased neuronal survival (*p=0.0373).

Conclusions

These experiments suggest that modulating dysfunctional RBP biology through KPT-276 restores RBP function and is a potential therapeutic, which increases neuronal survival and decreases neurodegeneration and clinical disease severity.

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Presenter Of 1 Presentation

Pathogenesis – Neurodegeneration Oral Presentation

YI01.03 - Inhibition of neuronal RNA binding protein dysfunction as a treatment for neurodegeneration in multiple sclerosis

Speakers
Presentation Number
YI01.03
Presentation Topic
Pathogenesis – Neurodegeneration
Lecture Time
11:24 - 11:36

Abstract

Background

Dysfunctional RNA binding proteins (RBPs), including heterogeneous nuclear ribonucleoprotein A1 (A1), are key pathological features of numerous neurologic diseases. Recently, evidence suggests that dysfunctional RBP biology, including mislocalization of the RBP from its homeostatic nuclear location to the cytoplasm, stress granule (SG) formation, and changes in RNA metabolism, are associated with neurodegeneration and worsened disease in multiple sclerosis (MS) and its models, such as experimental autoimmune encephalomyelitis (EAE).

Objectives

We hypothesized that correcting dysfunctional RBP biology with the nuclear export inhibitor, KPT-276, would restore A1 function by decreasing its nucleocytoplasmic mislocalization and reduce SG formation and neurodegeneration in spinal cord neurons from EAE animals as compared to vehicle controls.

Methods

C57BL/6 female mice were immunized with myelin oligodendrocyte glycoprotein (MOG35-55) to induce EAE. Upon reaching a clinical score of 2.5, mice were treated with KPT-276 (75 mg/kg, oral gavage) or vehicle control every other day for a total of six treatments. Two days following the final treatment, spinal cords were harvested and analyzed using immunofluorescence for A1 localization and SG formation in neurons as well as markers of neurodegeneration.

Results

EAE mice treated with KPT-276 showed a decrease in clinical score severity as compared to vehicle control EAE mice. Furthermore, mice treated with KPT-276 showed a significant reduction in the number of neurons with A1 mislocalization (*p=0.0351), the amount of A1 in the cytoplasm (*p=0.0341), and SG formation (*p=0.0208) as compared to vehicle mice. In the same areas of KPT-276 treated mice where there was a reduction in these features of dysfunctional RBP biology, there was a significant increase in the number of neurons indicative of increased neuronal survival (*p=0.0373).

Conclusions

These experiments suggest that modulating dysfunctional RBP biology through KPT-276 restores RBP function and is a potential therapeutic, which increases neuronal survival and decreases neurodegeneration and clinical disease severity.

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