Urine proteomics analysis of patients with neuronal ceroid lipofuscinoses

Katharina Iwan; Robert Clayton; Philippa Mills; Barbara Csanyi; Paul Gissen; Sara E Mole; David N Palmer; Kevin Mills; Wendy E Heywood

doi:10.1016/j.isci.2020.102020

Urine proteomics analysis of patients with neuronal ceroid lipofuscinoses

iScience. 2020 Dec 31;24(2):102020. doi: 10.1016/j.isci.2020.102020. eCollection 2021 Feb 19.

Authors

Katharina Iwan¹, Robert Clayton¹, Philippa Mills^{1

2}, Barbara Csanyi³, Paul Gissen^{1

2

3}, Sara E Mole^{1

4}, David N Palmer⁵, Kevin Mills^{1

2}, Wendy E Heywood^{1

2}

Affiliations

¹ Inborn Errors of Metabolism Section, Genetics & Genomic Medicine Unit, Great Ormond Street Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK.
² NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, London, UK.
³ Great Ormond Street Hospital for Children, London, UK.
⁴ MRC Laboratory for Molecular Cell Biology, University College London, London, UK.
⁵ Department of Molecular Biosciences, Agriculture and Life Sciences Faculty, University Lincoln 7647, Canterbury, New Zealand.

Abstract

The neuronal ceroid lipofuscinoses (NCL) are a group of 13 rare neurodegenerative disorders characterized by accumulation of cellular storage bodies. There are few therapeutic options, and existing tests do not monitor disease progression and treatment response. However, urine biomarkers could address this need. Proteomic analysis of CLN2 patient urine revealed activation of immune response pathways and pathways associated with the unfolded protein response. Analysis of CLN5 and CLN6 sheep model urine showed subtle changes. To confirm and investigate the relevance of candidate biomarkers a targeted LC-MS/MS proteomic assay was created. We applied this assay to additional CLN2 samples as well as other patients with NCL (CLN1, CLN3, CLN5, CLN6, and CLN7) and demonstrated that hexosaminidase-A, aspartate aminotransferase-1, and LAMP1 are increased in NCL samples and betaine-homocysteine S-methyltransferase-1 was specifically increased in patients with CLN2. These proteins could be used to monitor the effectiveness of future therapies aimed at treating systemic NCL disease.

Keywords: Disease; Proteomics; Systems Biology.

Grants and funding

MR/R025134/1/MRC_/Medical Research Council/United Kingdom