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Neurons are extremely energy demanding cells and highly dependent on the mitochondrial oxidative phosphorylation (OXPHOS) system. Mitochondria generate the energetic potential via the respiratory complexes I to IV, which constitute the electron transport chain (ETC), together with complex V. These redox reactions release energy in the form of ATP and also generate reactive oxygen species (ROS) that are involved in cell signaling but can eventually lead to oxidative stress. Complex I (CI or NADH:ubiquinone oxidoreductase) is the largest ETC enzyme, containing 44 subunits and the main contributor to ROS production. In recent years, the structure of the CI has become available and has provided new insights into CI assembly. A number of chaperones have been identified in the assembly and stability of the mature holo-CI, although they are not part of its final structure. Interestingly, CI dysfunction is the most common OXPHOS disorder in humans and defects in the CI assembly process are often observed. However, the dynamics of the events leading to CI biogenesis remain elusive, which precludes our understanding of how ETC malfunctioning affects neuronal integrity. Here, we review the current knowledge of the structural features of CI and its assembly factors and the potential role of CI misassembly in human disorders such as Complex I Deficiencies or Alzheimer's and Parkinson's diseases.

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Introduction: RNS60 is a novel immune-modulatory agent that has shown neuroprotective effects in amytrophic lateral sclerosis (ALS) preclinical models. RNS60 is administered by weekly intravenous infusion and daily nebulization. The objective of this pilot open-label trial was to test the feasibility, safety, and tolerability of long-term RNS60 administration in ALS patients. Methods: The planned treatment duration was 23 weeks and the primary outcomes were safety and tolerability. Secondary outcomes included PBR28 positron emission tomography (PET) imaging and plasma biomarkers of inflammation. Results: Sixteen participants with ALS received RNS60 and 13 (81%) completed 23 weeks of RNS60 treatment. There were no serious adverse events and no participants withdrew from the trial due to drugrelated adverse events. There were no significant changes in the biomarkers. Discussion: Long-term RNS60 administration was safe and well-tolerated. A large, multicenter, phase II trial of RNS60 is currently enrolling participants to test the effects of RNS60 on ALS biomarkers and disease progression.Muscle Nerve 59: [303][304][305][306][307][308] 2019 Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Loss of motor neurons leads to progressive paralysis of voluntary muscles and death, usually within 3-5 years after symptom onset. 1 Although there are 2 drugs approved by the United States Food and Drug Administration (FDA) to treat ALS, riluzole, and edaravone, the availability of new treatments for ALS continues to be an unmet medical need. 2,3 Neuroinflammation is increasingly implicated in ALS pathogenesis, 4-9 including activation of circulating monocytes, 9-13 lymphocytic infiltration, 14 and microglial activation in the central nervous system (CNS). 7,8 Mouse models of ALS show that activation of microglia and influx of T-lymphocytes into the CNS occur before symptom onset 4,9,15 and brain imaging in ALS patients reveals that neuroinflammation localizes to the motor regions. 7,8,16 Emerging evidence points to Tlymphocytes as key players in ALS progression. Among different lymphocytic subpopulations, regulatory Tlymphocytes (Tregs) are CD4 + CD25 high FOXP3 + cells that normally suppress proinflammatory responses and hold neuroinflammation in check. 5 In ALS patients, Treg suppressive function is impaired and the Treg transcription factor FOXP3 is reduced. Reduction in Treg function and FOXP3 expression correlates with faster ALS progression. [17][18][19] RNS60 is a novel immune-modulatory agent with neuroprotective properties in several in vitro and in vivo models of neurodegeneration, 20-26 including preclinical models of ALS. 27 In SOD1 G93A transgenic mice, RNS60 treatment resulted in upregulation of FOXP3-expressing Tregs and activation of protective astrocytes and microglia, which rescued the motor neurons and ameliorated disease progression. 27 These findings prompted translational efforts to human disease.The preliminary safety of RNS60 was previously established in a series of phase I tri...