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Comparative proteomic profiling reveals mechanisms for early spinal cord vulnerability in CLN1 disease

Nelvagal, HR; Hurtado, ML; Eaton, SL; Kline, RA; Lamont, DJ; Sands, MS; Wishart, TM; (2020) Comparative proteomic profiling reveals mechanisms for early spinal cord vulnerability in CLN1 disease. Scientific Reports , 10 (1) , Article 15157. 10.1038/s41598-020-72075-7. Green open access

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Abstract

CLN1 disease is a fatal inherited neurodegenerative lysosomal storage disease of early childhood, caused by mutations in the CLN1 gene, which encodes the enzyme Palmitoyl protein thioesterase-1 (PPT-1). We recently found significant spinal pathology in Ppt1-deficient (Ppt1−/−) mice and human CLN1 disease that contributes to clinical outcome and precedes the onset of brain pathology. Here, we quantified this spinal pathology at 3 and 7 months of age revealing significant and progressive glial activation and vulnerability of spinal interneurons. Tandem mass tagged proteomic analysis of the spinal cord of Ppt1−/−and control mice at these timepoints revealed a significant neuroimmune response and changes in mitochondrial function, cell-signalling pathways and developmental processes. Comparing proteomic changes in the spinal cord and cortex at 3 months revealed many similarly affected processes, except the inflammatory response. These proteomic and pathological data from this largely unexplored region of the CNS may help explain the limited success of previous brain-directed therapies. These data also fundamentally change our understanding of the progressive, site-specific nature of CLN1 disease pathogenesis, and highlight the importance of the neuroimmune response. This should greatly impact our approach to the timing and targeting of future therapeutic trials for this and similar disorders.

Type: Article
Title: Comparative proteomic profiling reveals mechanisms for early spinal cord vulnerability in CLN1 disease
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/s41598-020-72075-7
Publisher version: https://doi.org/10.1038/s41598-020-72075-7
Language: English
Additional information: This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: Animals, Disease Models, Animal, Disease Progression, Humans, Membrane Proteins, Mice, Mice, Inbred C57BL, Mice, Knockout, Neuronal Ceroid-Lipofuscinoses, Protein Array Analysis, Proteome, Spinal Cord, Thiolester Hydrolases
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharmacology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
URI: https://discovery.ucl.ac.uk/id/eprint/10144989
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