Respiratory Deficiency in the Optn−/−Mouse, A Novel Model of Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a devastating and fatal neurodegenerative disease with no current cure. Patients with ALS die 3–5 years after diagnosis when they ultimately succumb to inadequate ventilation, hypoxia, and respiratory failure. Several genes associated with ALS have recently been discovered. One of these genes encodes optineurin (OPTN) which is associated with neurodegeneration in both ALS and glaucoma. Optineurin has multiple roles in various biochemical pathways such as regulation of inflammation and autophagy. Through these functions, OPTN appears to be neuroprotective but the exact mechanism by which loss of OPTN results in progressive neural degeneration and respiratory failure in ALS is still unclear.Since respiratory pathology is a significant cause of morbidity and mortality in ALS, this study sought to characterize the respiratory pathology in a novel ALS mouse model – the Optn−/− mouse. The hypothesis driving this work is that the Optn−/− mouse has respiratory insufficiency due to degeneration of the respiratory motor unit – motor neuron, nerve, neuromuscular junction and muscle. Whole body plethysmography (WBP) was used to assess breathing at baseline and during a respiratory challenge with hypercapnic and hypoxic conditions (FiCO2: 0.07, FiO2: 0.10; nitrogen balance). During the respiratory challenge, compared to the WT mice, Optn−/− mice had significantly lower peak inspiratory flow and peak expiratory flow. Peak inspiratory flow and peak expiratory flow are indirect measures of inspiratory and expiratory muscle strength. Furthermore, throughout the challenge period Optn−/− mice spent a greater amount of time in apnea indicating pathology in the respiratory control centers. The weakness and pathology in control of breathing during the respiratory challenge progresses as the mice age. Post mortem immunohistochemical studies of the neuromuscular junctions within the diaphragm showed that Optn−/− mice had fragmented synaptotagmin staining indicating presynaptic degeneration. Finally, the hypoglossal nerves of Optn−/− mice had significantly reduced g‐ratio which indicates pathology and decompaction of myelin sheaths. In conclusion, the Optn−/− ALS mouse model displays respiratory insufficiency, aberrant control of breathing, and increased nerve demyelination.Support or Funding InformationR21 NS098131‐02 (MKE) and K08HD077040‐07 (MKE)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.