A Comprehensive NMR Analysis of Serum and Fecal Metabolites in Familial Dysautonomia Patients Reveals Significant Metabolic Perturbations

Author:

Costello Stephanann M.1ORCID,Cheney Alexandra M.1ORCID,Waldum Annie1,Tripet Brian1,Cotrina-Vidal Maria2,Kaufmann Horacio2,Norcliffe-Kaufmann Lucy2,Lefcort Frances3,Copié Valérie1ORCID

Affiliation:

1. Department of Chemistry and Biochemistry, Montana State University, Bozeman, MT 59717, USA

2. Department of Neurology, New York University School of Medicine, New York, NY 10017, USA

3. Department of Microbiology and Cell Biology, Montana State University, Bozeman, MT 59717, USA

Abstract

Central metabolism has a profound impact on the clinical phenotypes and penetrance of neurological diseases such as Alzheimer’s (AD) and Parkinson’s (PD) diseases, Amyotrophic Lateral Sclerosis (ALS) and Autism Spectrum Disorder (ASD). In contrast to the multifactorial origin of these neurological diseases, neurodevelopmental impairment and neurodegeneration in Familial Dysautonomia (FD) results from a single point mutation in the ELP1 gene. FD patients represent a well-defined population who can help us better understand the cellular networks underlying neurodegeneration, and how disease traits are affected by metabolic dysfunction, which in turn may contribute to dysregulation of the gut–brain axis of FD. Here, 1H NMR spectroscopy was employed to characterize the serum and fecal metabolomes of FD patients, and to assess similarities and differences in the polar metabolite profiles between FD patients and healthy relative controls. Findings from this work revealed noteworthy metabolic alterations reflected in energy (ATP) production, mitochondrial function, amino acid and nucleotide catabolism, neurosignaling molecules, and gut-microbial metabolism. These results provide further evidence for a close interconnection between metabolism, neurodegeneration, and gut microbiome dysbiosis in FD, and create an opportunity to explore whether metabolic interventions targeting the gut–brain–metabolism axis of FD could be used to redress or slow down the progressive neurodegeneration observed in FD patients.

Funder

National Institutes of Health

Alfred P. Sloan Foundation program

the Montana INBRE Native American Graduate Fellowship

Molecular Biosciences Program from Montana State University

NIH Shared Instrumentation Grant (SIG) program

National Science Foundation

Murdock Charitable Trust Foundation

MSU’s Office of the Vice President for Research and Economic Development

Publisher

MDPI AG

Subject

Molecular Biology,Biochemistry,Endocrinology, Diabetes and Metabolism

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