Regulation of pro-degenerative nicotinamide mononucleotide in Drosophila neurons
Description: Nicotinamide adenine dinucleotide (NAD+) metabolism is life-essential and required for a multitude of molecular mechanisms. Its dysregulation affects many cellular processes, including but not limited to neuronal fitness. Declining NAD+ metabolism contributes to various neurodegenerative diseases and is also a critical driver of axon degeneration. Thus, bolstering NAD+ metabolism serves as an attractive neuroprotective therapeutic approach.The NAD+ precursor nicotinamide mononucleotide (NMN) and its vitamin B3 derivatives–colloquially known as niacin–are widely used as dietarily-supplemented NAD+ boosters. Niacin and NMN are the substrates of a single enzyme–NMNAT1-3 in mammals and dNmnat in flies–for NAD+ synthesis to promote healthy aging and longevity. However, recent work demonstrated a surprising pro-degenerative role of NMN, as its accumulation results in the degeneration of axons and neurons. NMN is, therefore, at the intersection of healthy aging/longevity and axon-/neuro-degeneration. Thus, a better understanding of endogenous NMN synthesis, exogenous supply, and its regulation in neurons is needed.This research proposal addresses how levels of NMN are established and regulated in axons and neurons in two specific projects in the fruit fly Drosophila. Project A aims to investigate the supply of NMN in programmed axon degeneration signaling in severed axons. A Ph.D. student will explore the contribution of NMN synthesis and uptake, as well as its visualization in axons. Project B aims to establish how pro-degenerative NMN levels are regulated in neurons. A PostDoc will take advantage of an in vivo sensitized background–with elevated neuronal NMN due to low dNmnat activity resulting in neurodegeneration–to dissect the impact of dietarily-supplemented NMN, explore the benefits of abolishing endogenous NMN by genetic manipulations, and directly measure and analyze the affected neuronal NMN and total NAD+ homeostasis. The proposed investigations are based on state-of-the-art approaches that include CRISPR/Cas9 technology, distinct pharmacological, dietary, and genetic manipulations of the NAD+ metabolic flux, and novel genetically encoded fluorescent biosensors.This proposal aims to expand the current knowledge by investigating endogenous pro-degenerative NMN synthesis and its exogenous supply routes into neurons and axons. Providing insights into how NMN toxicity is established and how it contributes to axon degeneration and neurodegeneration in conditions of impaired NAD+ metabolism may lead to novel therapeutic interventions for neurodegenerative disorders and other age-related diseases.
Amount: CHF 885,800
Funding type: research
Funder scheme: Project funding
Start date: 2025-10-01
End date: 2029-09-30
Investigator: Neukomm, Lukas
Institution: University of Lausanne – LA
Subfield: Geriatrics and Gerontology
Field: Medicine
Domain: Health Sciences
Funded outputs count: 0
Funder award ID: 10004522
OpenAlex ID: G652739370