Pregnancy-associated plasma protein-aa promotes neuron survival by regulating mitochondrial function

Abstract

20A neuron's longevity is regulated by both extracellular molecular factors and the regulation of its 21 intracellular functions, including mitochondrial activity. It remains poorly understood which 22 extracellular factors promote neuron survival by influencing mitochondrial function. Through 23 zebrafish mutant analysis, we reveal a novel extracellular neuronal survival factor: Pregnancy-24 associated plasma protein-aa (Pappaa). Neurons in pappaa mutant larvae die precociously and exhibit 25 multiple mitochondrial defects, including elevated mitochondrial calcium, membrane potential, and 26 reactive oxygen species production (ROS). In pappaa mutants, neuron loss is exacerbated by 27 stimulation of mitochondrial calcium load or ROS production and suppressed by exposure to a 28 mitochondrial ROS scavenger. As a secreted metalloprotease, Pappaa stimulates local insulin-like 29 growth factor 1 (IGF1) signaling; a known regulator of mitochondrial function and neuron survival. In 30 pappaa mutants, neurons show reduced IGF1-receptor activity and neuron loss is attenuated by 31 stimulation of IGF1 signaling. These results suggest Pappaa-IGF1 signaling promotes neuron survival 32 by regulating mitochondrial function. 34Without a sufficient regenerative capacity, a nervous system's form and function critically depends 35 on molecular and cellular mechanisms that promote neuron longevity. A neuron's survival is 36 challenged by its own energy demands. Considerable energy is required for basic neuron functions, 37 including maintaining membrane potential, propagating electrical signals, and coordinating the release 38 and uptake of neurotransmitters (Halliwell, 2006; Kann and Kovács, 2007; Howarth et al., 2012). A 39 neuron's metabolic energy is primarily supplied by mitochondrial oxidative phosphorylation, a process 40 in which the flow of electrons across the electron transport chain produces adenosine triphosphate 41 (ATP) (Kann and Kovács, 2007). Although this process is essential to neuron survival, a consequence 42 of mitochondrial oxidative phosphorylation is the generation of cytotoxic reactive oxygen species 43 (ROS). The oxidative stress caused by ROS accumulation damages vital cell components including 44 DNA, proteins, and lipids (Schieber and Chandel, 2014). Neurons are particularly vulnerable to 45 oxidative stress due not only to their energy needs and thereby ROS production, but also to their 46 relatively insufficient antioxidant capacity compared to other cell types (Halliwell, 1992). Cumulative 47 oxidative stress can yield neuron loss, as observed in aging and neurodegenerative disorders including 48 Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic lateral sclerosis (ALS) (Perry 49 et al., 2002; Barber et al., 2006; Mattson and Magnus, 2006; Blesa et al., 2015). Thus, regulation of 50 mitochondrial ROS production and a neuron's capacity to minimize oxidative stress, are critical 51 determinants of neuron survival. 52The insulin-like growth factor-1 (IGF1) signaling ...