Fibroblast bioenergetics to classify amyotrophic lateral sclerosis patients

Molecular Neurodegeneration

卷:12

Hiroshi Mitsumoto¹  Jonathan C. Hupf¹  Jonathan D. Glass²  Chadwick M. Hales²  Nicholas J. Maragakis³  Timothy M. Miller⁴  John M. Ravits⁵  Steven Gross⁶  Andrea J. Arreguin⁷  Steven A. Cajamarca⁷  Giovanni Manfredi⁷  Kirsten G. Bredvik⁷  Hibiki Kawamata⁷  Csaba Konrad⁷ 

[1] Department of Neurology, Columbia University;

[2] Department of Neurology, Emory School of Medicine;

[3] Department of Neurology, Johns Hopkins University School of Medicine;

[4] Department of Neurology, Washington University School of Medicine;

[5] Department of Neuroscience, University of California San Diego;

[6] Department of Pharmacology, Weill Cornell Medicine;

[7] Feil Family Brain and Mind Research Institute, Weill Cornell Medicine;

关键词: Bioenergetics;    Mitochondria;    ALS;    Fibroblasts;    PLS;    Machine learning;   

DOI  :  10.1186/s13024-017-0217-5

来源: DOAJ

【 摘 要 】

Abstract Background The objective of this study was to investigate cellular bioenergetics in primary skin fibroblasts derived from patients with amyotrophic lateral sclerosis (ALS) and to determine if they can be used as classifiers for patient stratification. Methods We assembled a collection of unprecedented size of fibroblasts from patients with sporadic ALS (sALS, n = 171), primary lateral sclerosis (PLS, n = 34), ALS/PLS with C9orf72 mutations (n = 13), and healthy controls (n = 91). In search for novel ALS classifiers, we performed extensive studies of fibroblast bioenergetics, including mitochondrial membrane potential, respiration, glycolysis, and ATP content. Next, we developed a machine learning approach to determine whether fibroblast bioenergetic features could be used to stratify patients. Results Compared to controls, sALS and PLS fibroblasts had higher average mitochondrial membrane potential, respiration, and glycolysis, suggesting that they were in a hypermetabolic state. Only membrane potential was elevated in C9Orf72 lines. ATP steady state levels did not correlate with respiration and glycolysis in sALS and PLS lines. Based on bioenergetic profiles, a support vector machine (SVM) was trained to classify sALS and PLS with 99% specificity and 70% sensitivity. Conclusions sALS, PLS, and C9Orf72 fibroblasts share hypermetabolic features, while presenting differences of bioenergetics. The absence of correlation between energy metabolism activation and ATP levels in sALS and PLS fibroblasts suggests that in these cells hypermetabolism is a mechanism to adapt to energy dissipation. Results from SVM support the use of metabolic characteristics of ALS fibroblasts and multivariate analysis to develop classifiers for patient stratification.

【 授权许可】

Unknown