Mitochondrial dysregulation occurs early in ALS motor cortex with TDP-43 pathology and suggests maintaining NAD + balance as a therapeutic strategy.
Mukesh GautamAksu GunayNavdeep S ChandelP Hande OzdinlerPublished in: Scientific reports (2022)
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-43 A315T -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.
Keyphrases
- amyotrophic lateral sclerosis
- high performance liquid chromatography
- tandem mass spectrometry
- ultra high performance liquid chromatography
- liquid chromatography
- simultaneous determination
- ms ms
- mass spectrometry
- high resolution mass spectrometry
- solid phase extraction
- gas chromatography
- mental health
- oxidative stress
- public health
- mouse model
- spinal cord
- liquid chromatography tandem mass spectrometry
- high resolution
- metabolic syndrome
- type diabetes
- single cell
- skeletal muscle
- health information
- spinal cord injury
- insulin resistance
- social media