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

This study investigated th e secretome in the CLN6 (ceroid‐lipofuscinosis neuronal protein 6) variant of NCL. To investigate the CLN6 secretome, we co‐cultured neurons and glia isolated fromCln6nclf 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 – bothin vitro in co ‐cultures andin vivo in mouse plasma. InCln6nclf 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 candidatein vitro biomarkers. Importantly, thesein vitro changes show promise forin vivo translation, with Cathepsin L (CTSL) activity reduced in both co ‐cultures andCln6nclf plasma samples post gene ‐therapy. This work suggests the secretome plays a role in CLN6 pathogenesis and highlights its potential use as anin vitro model. Proteomic changes present a list of candidate biomarkers for monitoring disease and assessing potential therapeutics in future studies.
Source: Journal of Neurochemistry - Category: Neuroscience Authors: Tags: ORIGINAL ARTICLE Source Type: research