An altered secretome is an early marker of the pathogenesis of CLN6 Batten disease

Best, Hannah L., Clare, Alison J., McDonald, Kirstin O., Wicky, Hollie E. and Hughes, Stephanie M. 2021. An altered secretome is an early marker of the pathogenesis of CLN6 Batten disease. Journal of Neurochemistry 157 (3) , pp. 764-780. 10.1111/jnc.15285

PDF - Accepted Post-Print Version Download (663kB)

Abstract

Neuronal ceroid lipofuscinoses (NCLs) are a group of inherited childhood neurodegenerative disorders. In addition to the accumulation of auto-fluorescent storage material in lysosomes, NCLs are largely characterised by region-specific neuroinflammation that can predict neuron loss. These phenotypes suggest alterations in the extracellular environment—making the secretome an area of significant interest. This study investigated the secretome in the CLN6 (ceroid-lipofuscinosis neuronal protein 6) variant of NCL. To investigate the CLN6 secretome, we co-cultured neurons and glia isolated from Cln6nclf or Cln6± mice, and utilised mass spectrometry to compare protein constituents of conditioned media. The significant changes noted in cathepsin enzymes, were investigated further via western blotting and enzyme activity assays. Viral-mediated gene therapy was used to try and rescue the wild-type phenotype and restore the secretome—both in vitro in co-cultures and in vivo in mouse plasma. In Cln6nclf cells, proteomics revealed a marked increase in catabolic and cytoskeletal-associated proteins—revealing new similarities between the pathogenic signatures of NCLs with other neurodegenerative disorders. These changes were, in part, corrected by gene therapy intervention, suggesting these proteins as candidate in vitro biomarkers. Importantly, these in vitro changes show promise for in vivo translation, with Cathepsin L (CTSL) activity reduced in both co-cultures and Cln6nclf plasma samples post gene-therapy. This work suggests the secretome plays a role in CLN6 pathogenesis and highlights its potential use as an in vitro model. Proteomic changes present a list of candidate biomarkers for monitoring disease and assessing potential therapeutics in future studies.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Publisher:	Wiley
ISSN:	0022-3042
Date of First Compliant Deposit:	3 August 2021
Date of Acceptance:	17 December 2020
Last Modified:	07 Nov 2023 07:52
URI:	https://orca.cardiff.ac.uk/id/eprint/143115

Citation Data

Cited 2 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item