Acute traumatic brain injury does not exacerbate ALS in the SOD1 rat model TBI does not exacerbate ALS in SOD1 rat

2 Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease in which upper and lower 3 motor neurons degenerate leading to muscle atrophy, paralysis and death within 3 to 5 years of 4 onset. While a small percentage of ALS cases are genetically linked, the majority are sporadic 5 with unknown origin. Currently, etiological links are associated with disease onset without 6 mechanistic understanding. Of all the putative risk factors, however, head trauma has emerged 7 as a consistent candidate for initiating the molecular cascades of ALS. Here, we test the 8 hypothesis that traumatic brain injury (TBI) in the SOD1 transgenic rat model of ALS leads to 9 early disease onset and shortened lifespan. We demonstrate, however, that a one-time acute 10 focal injury caused by controlled cortical impact (CCI), does not affect disease onset or survival. 11 Establishing the negligible involvement of a single acute focal brain injury in an ALS rat model 12 increases the current understanding of the disease. Critically, untangling a single focal TBI from 13 multiple mild injuries provides a rationale for scientists and physicians to increase focus on 14 repeat injuries to hopefully pinpoint a contributing cause of ALS. 15 Significance statement 16 Here we show that a one-time focal traumatic brain injury does not affect the disease time17 course or survival in the SOD1 rat model of ALS. This is important, as head injury has 18 emerged as a strong candidate for initiating the neurodegenerative processes in ALS patients. 19 By showing a lack of effect of acute, moderate/severe focal traumatic brain injury in this 20 genetically pre-disposed model, focus can now be made on other types of CNS injuries 21 including mild repeat traumatic brain injury, or diffuse axonal injury to elucidate the involvement 22 of trauma in the initiation of SOD1 mutation-based ALS. 23 24