Altered Plasma Acylcarnitines and Amino Acids Profile in Spinocerebellar Ataxia Type 7

Abstract

Spinocerebellar ataxia type 7 (SCA7), a neurodegenerative disease characterized by cerebellar ataxia and retinal degeneration, is caused by an abnormal CAG repeat expansion in the ATXN7 gene coding region. The onset and severity of SCA7 are highly variable between patients, thus identification of sensitive biomarkers that accurately diagnose the disease and monitoring its progression are needed. With the aim of identified SCA7-specific metabolites with clinical relevance, we report for the first time, to the best of our knowledge, a metabolomics profiling of circulating acylcarnitines and amino acids in SCA7 patients. We identified 21 metabolites with altered levels in SCA7 patients and determined two different sets of metabolites with diagnostic power. The first signature of metabolites (Valine, Leucine, and Tyrosine) has the ability to discriminate between SCA7 patients and healthy controls, while the second one (Methionine, 3-hydroxytetradecanoyl-carnitine, and 3-hydroxyoctadecanoyl-carnitine) possess the capability to differentiate between early-onset and adult-onset patients, as shown by the multivariate model and ROC analyses. Furthermore, enrichment analyses of metabolic pathways suggest alterations in mitochondrial function, energy metabolism, and fatty acid beta-oxidation in SCA7 patients. In summary, circulating SCA7-specific metabolites identified in this study could serve as effective predictors of SCA7 progression in the clinics, as they are sampled in accessible biofluid and assessed by a relatively simple biochemical assay.

Spinocerebellar ataxia clinical trials: opportunities and challenges

“…While no fluid biomarkers have yet been validated for the SCAs, there are some promising candidates (Table 2 ). 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 The first candidate is the mutant protein itself in the case of the polyglutamine SCAs. In all these ataxias, the protein tends to accumulate and aggregate.…”

PathIN: an integrated tool for the visualization of pathway interaction networks

“…It is observed that 8 additional pathways (depicted in green colour) have been included in the underlying network. Indicatively, the “Phospholipase D signalling pathway” , which is one of the first neighbours of the “sphingolipid metabolism” has already been mentioned in studies related to ataxia [21] , [22] , [23] , as well as pathways related to fatty acids [24] , [25] . Analysis using the 3rd methodology resulted in a larger network (depicted in Fig.…”

Protein oxidation - Formation mechanisms, detection and relevance as biomarkers in human diseases

“…A method which reveals modification site, but not the type of modification is amino acid analysis. By analyzing hydrolysates of native and modified protein samples, the amino acid composition can provide information about the loss of parent proteins, but also the formation of products [ 101 ]. Various protocols for the analysis of amino acids exist using derivatization with dansyl chloride or ortho -phthalaldehyde and subsequent HPLC-FLD [ 102 , 103 ] or HPLC-UV [ 104 , 105 ] or preparation of butyl esters followed by ion-pair LC-MS/MS [ 106 ].…”