Pathogenesis and motor neuron degeneration of a novel disease associated with a P158A mutation in nampt

Active Project Grant Awarded Last action

Award ID
R01NS123023
Recipient
Awarding agency
Obligated
$6,405,876

Award facts

Completion date 96% complete
Place of performance
Columbia, MO 65211, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Nicotinamide adenine dinucleotide (NAD+) is a cofactor required for glycolysis, the tricarboxylic acid cycle (TCA) and enzymatic reaction in electron transport chain (etc). In mammalian cells, NAD+ salvage pathway, where nicotinamide phosphoribosyltransferase (nampt) is the rate-limiting enzyme, is the predominant pathway for NAD+ biosynthesis. Although the dysregulation of NAD+ in aging and neurodegerative diseases has been reported, genetic diseases caused by nampt variants have not been clinically recognized and understood. Here we identified the first case of an inherited neurological disease caused by a homozygous single nucleotide polymorphism (SNP), i.e., a P158A mutation in the coding region of nampt gene. The major clinical features of patients include impaired motor coordination, muscle weakness, atrophy of lower extremities, positive babinski sign. The patients were diagnosed as hereditary motor and sensory neuropathy involving axonal degeneration and neuromuscular junction (NMJ) dysfunction. Using skin-derived patient fibroblasts (p-FBS), our preliminary studies found that P158A mutation causes reduced bioenergetics, mitochondrial dysfunction, and decreased enzymatic activity of nampt for NAD+ biosynthesis compared with healthy control fibroblasts (c-FBS). The results indicate the pathological conditions related to the patients is initially resulted from bioenergetic stress and ultimately from neuronal and muscular degeneration. Thus, our project goal is to understand the pathogenesis and the mechanism of neuronal and muscular degeneration of this new disease. To achieve our goal, we generated many molecular tools including P158A-nampt mutant mice, c- & p-FBS-derived induced pluripotent stem cells (c- & p-ipscs including isogenic and patient like p-ipscs), and ipsc-induced motor neurons (c- & p- imns). We propose three specific aims. Aim 1 will test the hypothesis P158A mutation in nampt causes mitochondrial and synaptic dysfunction of p-imns. Using imns, we will study the effect of P158A mutation on cellular bioenergetics, glycolytic metabolism and mitochondrial respiration. We will also conduct combined metabolomic and transcriptional profiling to determine the molecular base of metabolic changes caused by P158A mutation. Aim 2 will test the hypothesis that P158A mutation in nampt causes MN degeneration. Using the mutant mice, we will study disease progression, upper and lower MN degeneration. We will use electrophysiological and two-photon (2-p) imaging to study the effect of P158A mutation on sensory response and cytosolic and mitochondrial CA2+ signaling. Aim 3 will test the hypothesis that P158A mutation in nampt causes NMJ abnormalities and muscle degeneration. We will assess structural and functional abnormalities of nmjs and muscle contractile response of semitendinosus muscles isolated from the symptomatic mutant mice. A human disease caused by nampt mutation has not been reported so far. Our application represents a first in-depth study on the pathogenesis and mechanism of motor neuron and muscle degeneration of a new neurological disease caused by a mutation in nampt gene.

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Subawards

Subrecipient Amount Awarded
West Virginia University Research Corporation "Use targeted metabolomics approach with gas/.iquid chromatography-mass spectrometry (GC/LC-MS) to quantify metabolites from induced motor neurons from… -$14,777
Rutgers, The State University Will provide advice and guidance on reprogramming of human fibroblasts to induced pluripotent stem cells (iPSCs) and their differentiation of motor neurons. $9,551
West Virginia University Research Corporation "Use targeted metabolomics approach with gas/.iquid chromatography-mass spectrometry (GC/LC-MS) to quantify metabolites from induced motor neurons from… $19,392
West Virginia University Research Corporation $19,050
Rutgers, The State University Will provide advice and guidance on reprogramming of human fibroblasts to induced pluripotent stem cells (iPSCs) and their differentiation of motor neurons. $14,490
West Virginia University Research Corporation "Use targeted metabolomics approach with gas/.iquid chromatography-mass spectrometry (GC/LC-MS) to quantify metabolites from induced motor neurons from… $18,717
Rutgers, The State University Will provide advice and guidance on reprogramming of human fibroblasts to induced pluripotent stem cells (iPSCs) and their differentiation of motor neurons. $40,983
West Virginia University Research Corporation "Use targeted metabolomics approach with gas/.iquid chromatography-mass spectrometry (GC/LC-MS) to quantify metabolites from induced motor neurons from… $36,471

Quick answers

Who received award R01NS123023?

R01NS123023 was awarded to University Of Missouri System by National Institute of Neurological Disorders and Stroke (National Institutes of Health) on February 15, 2022.

How much is award R01NS123023 worth?

$6,405,876 has been obligated on R01NS123023.

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