Impact of the NAD+ salvage pathway on the motor system and bioenergetics
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Nicotinamide adenine dinucleotide (NAD+) is a metabolite pivotal to numerous cellular functions, including energy metabolism, DNA repair, and protein modification. The majority of NAD+ is generated by the NAD+ salvage pathway, which is rate limited by nicotinamide phosphoribosyltransferase (NAMPT). NAMPT and the NAD+ salvage pathway are critical to most cell types, but are especially important to neuronal health and function. Additionally, the NAD+ salvage pathway is increasingly being investigated for being involved in neurodegenerative diseases. Recently, the importance of NAMPT to motor and neuromuscular junction (NMJ) activity and survival has been reported. However, how the NAD+ salvage pathway affects NMJ function and what metabolic pathway are dysregulated when the salvage pathway becomes impaired warrants further investigation. In Chapter one, I review intracellular NAD+ homeostasis, NAD+ salvage pathway enzymes, and the importance of NAD+ homeostasis in health and neurodegenerative diseases, specifically ALS. In Chapter two and Chapter three, I used inducible and conditional projection neuron-specific NAMPT knockout mouse, which previously was found to experience profound motor dysfunction and neuron loss. I investigated NMJ structure and function following NAMPT deletion and what benefits NMN administration produces. I also studied how the metabolic and transcriptional profiles in the motor cortex of these knockout mice are altered after NAMPT loss. In Chapter Four, based on the similar phenotypes between the NAMPT knockout mice and ALS mice and NAD+ reduction in ALS mouse model, I investigated how dietary NMN supplementation affects motor behavior and NMJ function in SOD1G93A ALS mice. Overall, the results from these studies provide novel insights into how the NAD+ salvage path is critical for NMJs and what metabolic stress and signaling pathways are responsible for the neuronal death after NAMPT deletion
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Ph. D.