Abstract
Mitochondrial defects result in dysregulation of metabolomics and energy homeostasis that are detected in upper motor neurons (UMNs) with TDP-43 pathology, a pathology that is predominantly present in both familial and sporadic cases of amyotrophic lateral sclerosis (ALS). While same mitochondrial problems are present in the UMNs of ALS patients with TDP-43 pathology and UMNs of TDP-43 mouse models, and since pathologies are shared at a cellular level, regardless of species, we first analyzed the metabolite profile of both healthy and diseased motor cortex to investigate whether metabolomic changes occur with respect to TDP-43 pathology. High-performance liquid chromatography, high-resolution mass spectrometry and tandem mass spectrometry (HPLC–MS/MS) for metabolite profiling began to suggest that reduced levels of NAD+ is one of the underlying causes of metabolomic problems. Since nicotinamide mononucleotide (NMN) was reported to restore NAD+ levels, we next investigated whether NMN treatment would improve the health of diseased corticospinal motor neurons (CSMN, a.k.a. UMN in mice). prpTDP-43A315T-UeGFP mice, the CSMN reporter line with TDP-43 pathology, allowed cell-type specific responses of CSMN to NMN treatment to be assessed in vitro. Our results show that metabolomic defects occur early in ALS motor cortex and establishing NAD+ balance could offer therapeutic benefit to UMNs with TDP-43 pathology.
Highlights
Mitochondria are best studied for their ability to generate energy, but they are essential for lipid homeostasis, ensuring proper C a+2 storage inside the cells, and maintaining metabolomic b alance[1–5]
Since mitochondrial defects have been broadly observed in many different diseases in which TDP-43 pathology is commonly detected, and because mitochondria are crucially important for maintaining metabolomic homeostasis, one of the key questions that remains unanswered is: “What are the metabolomic changes that occur with respect to TDP-43 pathology?” We investigated the metabolomic perturbations that occur in the motor cortex of prp-TDP-43A315T mice, a mouse model which recapitulates many aspects of TDP-43 pathology observed in amyotrophic lateral sclerosis (ALS) and ALS/FTLD patients[19]
Mitochondrial problems were present as early as P1517, and they were observed in the upper motor neurons (UMNs) of a broad spectrum of ALS patients with TDP-43 pathology[16]
Summary
Mitochondria are best studied for their ability to generate energy, but they are essential for lipid homeostasis, ensuring proper C a+2 storage inside the cells, and maintaining metabolomic b alance[1–5] With their multiple important functions, they serve as one of the key organelles for cellular health. Since mitochondrial defects have been broadly observed in many different diseases in which TDP-43 pathology is commonly detected, and because mitochondria are crucially important for maintaining metabolomic homeostasis, one of the key questions that remains unanswered is: “What are the metabolomic changes that occur with respect to TDP-43 pathology?” We investigated the metabolomic perturbations that occur in the motor cortex of prp-TDP-43A315T mice, a mouse model which recapitulates many aspects of TDP-43 pathology observed in ALS and ALS/FTLD patients[19]. Our results reveal early metabolomic problems in the motor cortex, and suggest that maintaining NAD+ balance could offer a therapeutic treatment strategy for diseased UMNs with TDP-43 pathology
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