Metabolic Profiling Reveals Biochemical Pathways and Potential Biomarkers of Spinocerebellar Ataxia 3.

Zhi-Hua Yang,Hai-Yang Luo,Cheng-Yuan Mao,Li-Na Zhou,Yu-Tao Liu,Chang-He Shi,Guo-Wang Xu,Yu-Ming Xu,Yu-Sheng Li,Jing Yang

doi:10.3389/fnmol.2019.00159

Abstract

Spinocerebellar ataxia 3, also known as Machado-Joseph disease (SCA3/MJD), is a rare autosomal-dominant neurodegenerative disease caused by an abnormal expansion of CAG repeats in the ATXN3 gene. In the present study, we performed a global metabolomic analysis to identify pathogenic biochemical pathways and novel biomarkers implicated in SCA3 patients. Metabolic profiling of serum samples from 13 preclinical SCA3 patients, 13 symptomatic SCA3 patients, and 15 healthy controls were mapped using ultra-high-performance liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry techniques. The symptomatic SCA3 patients showed a metabolic profile significantly distinct from those of the preclinical SCA3 patients and healthy controls. The principal differential metabolites were involved in the amino acid (AA) metabolism and fatty acid metabolism pathways. In addition, four candidate serum biomarkers, FFA 16:1 (palmitoleic acid), FFA 18:3 (linolenic acid), L-Proline and L-Tryptophan, were selected to discriminate between symptomatic SCA3 patients and healthy controls by receiver operator curve analysis with an area under the curve of 0.979. Our study demonstrates that symptomatic SCA3 patients present distinct metabolic profiles with perturbed AA metabolism and fatty acid metabolism, and FFA 16:1, FFA 18:3, L-Proline and L-Tryptophan are identified as potential disease biomarkers.

Highlights

Spinocerebellar ataxia 3 (SCA3) or Machado-Joseph disease (MJD) is the most common of the SCAs, with a worldwide prevalence of 1.5 cases per 100,000 individuals (Ruano et al, 2014)
For the non-ataxia features, muscle cramps could be detected in 30.7% (4/13) of pre-SCA3 carriers and 38.4% (5/13) of the symptomatic SCA3 patients, sensory disturbance in 15.4% (2/13) of pre-SCA3 carriers and 53.8% (7/13) of the symptomatic SCA3 patients, hyperreflexia in the lower limbs in 23.1% (3/13) of pre-SCA3 carriers and 61.5% (8/13) of the symptomatic SCA3 patients, hyporeflexia in the lower limbs in 15.4% (2/13) of pre-SCA3 carriers and 30.7 (4/13) of the symptomatic SCA3 patients, extrapyramidal signs in 15.4% (2/13) of pre-SCA3 carriers and 53.8% (7/13) of the symptomatic SCA3 patients, extensor plantar reflex and impaired vibration sense in 53.8% (7/13) and 7.7% (1/13) of symptomatic SCA3 patients, respectively, while none in pre-SCA3 carriers
This study presents the first evaluation of the serum metabolomic profile of patients with SCA3

Summary

Introduction

Spinocerebellar ataxia 3 (SCA3) or Machado-Joseph disease (MJD) is the most common of the SCAs, with a worldwide prevalence of 1.5 cases per 100,000 individuals (Ruano et al, 2014). It is caused by an abnormal expansion of CAG repeats in the ATXN3 gene and is characterized by a wide range of clinical features, including progressive ataxia, spasticity, ophthalmoplegia, and extrapyramidal signs (Durr et al, 1996; Riess et al, 2008; Schmitz-Hübsch et al, 2008; Jacobi et al, 2011; Costa Mdo and Paulson, 2012; Paulson, 2012). Identification of molecular pathways and biomarkers may prove beneficial in uncovering pathogenic mechanisms, identifying drug targets, monitoring disease progression, and assessing therapeutic effects (Lima and Raposo, 2018)

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Conclusion