Amyotrophic Lateral Sclerosis (ALS) is a devastating and fatal neurodegenerative disease with no current cure. Focal weakness eventually progresses to global muscle weakness and paralysis, but the exact etiology of these events remains unknown. Many patients die when they ultimately succumb to inadequate ventilation, hypoxia, and respiratory failure. Recently, the gene for optineurin (OPTN) was found to be associated with neurodegeneration in ALS. Patients with OPTN mutations show an onset of ALS from 30 to 60 years of age and have a slowly progressive disease before they eventually die of respiratory failure. The etiology of OPTN deficiency induced respiratory failure remains unknown and will be a focus of Aim 1 of this application. In addition, in Aim 2, we will look at the impact of hypoxia (or low oxygen levels) on disease initiation and progression. In ALS, impaired breathing due to progressive weakness of the respiratory muscles leads to chronic intermittent hypoxia. However, prior to diagnosis, we propose that hypoxia may also play a role in triggering the disease onset and exacerbating motor weakness in OPTN deficient patients. At the cellular level, hypoxia induces mitochondrial degradation, activates autophagy and induces cell death. Interestingly, OPTN regulates mitochondrial degradation, autophagy and cell death. Since OPTN is essential in regulating autophagy, we propose that in the absence of OPTN, the effects of chronic intermittent hypoxia (CIH) will be amplified and will result in protein aggregation and cellular disruption in respiratory motoneurons. This disruption will further exacerbate breathing impairment. Thus, the fundamental hypothesis driving this proposal is that OPTN deficiency impairs respiratory function, and exposure to CIH triggers early disease onset and accelerates respiratory pathology. In order to test our hypothesis, we will use OPTN knock out mice (Optn-/-) generated by Henry Tseng (co-I). Similar to pathology experienced by ALS patients, these mice exhibit deficits in balance, coordination, and motor impairment that progressively deteriorates with age. Optn-/- mice provide an important opportunity and an ideal tool to study stress-dependent mechanisms that exacerbate neurodegeneration and respiratory function in ALS.
Two specific aims will be accomplished using the Optn-/- mouse model:
Aim 1 : To identify the impact of OPTN deficiency on respiratory function and respiratory motoneurons, nerves, and muscle in ALS and Aim 2: To assess the impact of CIH on disease onset and progression in OPTN deficiency. The proposed experiments address a comprehensive evaluation of respiratory function including spontaneous breathing and respiratory nerve output, as well as biochemical and histological assessment of respiratory motor units. This R21 proposal will combine the respiratory physiology and ALS mouse model experience of the PI (ElMallah), with the neurobiology and optineurin experience of the co-I (Tseng). Project Summary/Abstract Page 1

Public Health Relevance

Amyotrophic Lateral Sclerosis (ALS) is a devastating and fatal disease for which there is no cure. The cause of ALS remains unclear but several new genes have recently been identified. One such gene encodes for the optineurin protein. Patients with ALS who have optineurin deficiency experience swallowing and breathing problems and eventually die from respiratory failure but why this respiratory failure occurs is unknown. This application uses an optineurin deficient mouse model to study the mechanisms that contribute to ALS breathing pathology with the goal of identifying future therapeutic targets. In addition, we will explore the role of low oxygen levels in initiating and exacerbating the breathing difficulties and overall disease progression. Information gained from this proposal will provide a better understanding of how optineurin deficiency results in ALS and will guide future therapies for this devastating condition. Project Narrative Page 1

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Respiratory Integrative Biology and Translational Research Study Section (RIBT)
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Gubitz, Amelie
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Duke University
Schools of Medicine
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