Targeted metabolomics revealed changes in phospholipids during the development of neuroinflammation in Abcd1^tm1Kds mice and X‐linked adrenoleukodystrophy patients

Abstract

X‐linked adrenoleukodystrophy (X‐ALD) is the most common leukodystrophy. Despite intensive research in recent years, it remains unclear, what drives the different clinical disease courses. Due to this missing pathophysiological link, therapy for the childhood cerebral disease course of X‐ALD (CCALD) remains symptomatic; the allogenic hematopoietic stem cell transplantation or hematopoietic stem‐cell gene therapy is an option for early disease stages. The inclusion of dried blood spot (DBS) C26:0‐lysophosphatidylcholine to newborn screening in an increasing number of countries is leading to an increasing number of X‐ALD patients diagnosed at risk for CCALD. Current follow‐up in asymptomatic boys with X‐ALD requires repetitive cerebral MRIs under sedation. A reliable and easily accessible biomarker that predicts CCALD would therefore be of great value. Here we report the application of targeted metabolomics by AbsoluteIDQ p180‐Kit from Biocrates to search for suitable biomarkers in X‐ALD. LysoPC a C20:3 and lysoPC a C20:4 were identified as metabolites that indicate neuroinflammation after induction of experimental autoimmune encephalitis in the serum of Abcd1tm1Kds mice. Analysis of serum from X‐ALD patients also revealed different concentrations of these lipids at different disease stages. Further studies in a larger cohort of X‐ALD patient sera are needed to prove the diagnostic value of these lipids for use as early biomarkers for neuroinflammation in CCALD patients.

ABCD1 and X‐linked adrenoleukodystrophy: A disease with a markedly variable phenotype showing conserved neurobiology in animal models

“…In search for disease biomarkers, VLCFAs incorporated at the sn-1 position of phosphatidylcholine and phosphatidylethanolamine were found to be enriched in Abcd1 null mice, similar to a profile seen in fibroblasts from Zellweger spectrum disorder patients (Hama et al, 2018). More recently, the induction of experimental autoimmune encephalitis (EAE, achieved by injecting a truncated MOG peptide with bacterial adjuvant) in such mice resulted in decrease of both serum C20:3-LPC and C20:4-LPC in subjects in which EAE resulted in paralysis compared with null mice unaffected by the EAE or control (Kettwig et al, 2021). Translating to humans, a twofold decrease in both species was observed only in ccALD patients prior to MRI changes but not in those with positive Loes score at the time of analysis, complicating the interpretation of these findings as X-ALD-related neuroinflammation biomarkers.…”

Gardenin A treatment attenuates inflammatory markers, synuclein pathology and deficits in tyrosine hydroxylase expression and improves cognitive and motor function in A53T-α-syn mice

“…Previous studies also indicated the effects of flavonoids on the metabolism of lipids in mice [ 54 ]. These studies showed that flavonoids and their metabolites can attach themselves to the lipid bilayer or interact with membrane receptors, which in turn modify the bilayer lipid profile [ 54 – 56 ]. The interaction and penetration of polyphenols with lipid bilayers depend on the structures and concentrations of the polyphenols, the compositions of the lipids, and other factors [ 57 ].…”

Gardenin A improves cognitive and motor function in A53T-α-syn mice

“…Previous studies also indicated the effects of flavonoids on the metabolism of lipids in mice (52). These studies showed that flavonoids and their metabolites can attach themselves to the lipid bilayer or interact with membrane receptors, which in turn modify the bilayer lipid profile (52-54). The interaction and penetration of polyphenols with lipid bilayers depend on the structures and concentrations of the polyphenols, the compositions of the lipids, and other factors (55).…”