PMID- 32938982 OWN - NLM STAT- MEDLINE DCOM- 20201221 LR - 20211111 IS - 2045-2322 (Electronic) IS - 2045-2322 (Linking) VI - 10 IP - 1 DP - 2020 Sep 16 TI - Comparative proteomic profiling reveals mechanisms for early spinal cord vulnerability in CLN1 disease. PG - 15157 LID - 10.1038/s41598-020-72075-7 [doi] LID - 15157 AB - 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. FAU - Nelvagal, Hemanth R AU - Nelvagal HR AD - Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University in St Louis, School of Medicine, 660 S Euclid Ave, St Louis, MO, 63110, USA. AD - Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK. FAU - Hurtado, Maica Llavero AU - Hurtado ML AD - The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian, UK. FAU - Eaton, Samantha L AU - Eaton SL AD - The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian, UK. FAU - Kline, Rachel A AU - Kline RA AD - The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian, UK. FAU - Lamont, Douglas J AU - Lamont DJ AD - FingerPrints Proteomics Facility, College of Life Sciences, University of Dundee, Dundee, UK. FAU - Sands, Mark S AU - Sands MS AD - Department of Genetics, Washington University in St Louis, School of Medicine, 660 S Euclid Ave, St Louis, MO, 63110, USA. AD - Department of Medicine, Washington University in St Louis, School of Medicine, 660 S Euclid Ave, St Louis, MO, 63110, USA. FAU - Wishart, Thomas M AU - Wishart TM AD - The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian, UK. FAU - Cooper, Jonathan D AU - Cooper JD AD - Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University in St Louis, School of Medicine, 660 S Euclid Ave, St Louis, MO, 63110, USA. cooperjd@wustl.edu. AD - Department of Genetics, Washington University in St Louis, School of Medicine, 660 S Euclid Ave, St Louis, MO, 63110, USA. cooperjd@wustl.edu. AD - Department of Neurology, Washington University in St Louis, School of Medicine, 660 S Euclid Ave, St Louis, MO, 63110, USA. cooperjd@wustl.edu. AD - Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK. cooperjd@wustl.edu. LA - eng GR - R01 NS100779/NS/NINDS NIH HHS/United States GR - NINDS 043205/NH/NIH HHS/United States GR - Institute Strategic Programme (ISPG/1 18-22)/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom GR - Institute Strategic Programme (ISPG/5 12-17)/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20200916 PL - England TA - Sci Rep JT - Scientific reports JID - 101563288 RN - 0 (Membrane Proteins) RN - 0 (Proteome) RN - EC 3.1.2.- (Thiolester Hydrolases) RN - EC 3.1.2.22 (PPT1 protein, human) RN - EC 3.1.2.22 (palmitoyl-protein thioesterase) SB - IM MH - Animals MH - Disease Models, Animal MH - Disease Progression MH - Humans MH - Membrane Proteins/*genetics MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Neuronal Ceroid-Lipofuscinoses/*genetics/*metabolism/pathology MH - Protein Array Analysis MH - Proteome/genetics/metabolism MH - Spinal Cord/*metabolism/pathology MH - Thiolester Hydrolases/deficiency/*genetics PMC - PMC7495486 COIS- JDC has received research support from BioMarin Pharmaceutical Inc. in addition to Abeona Therapeutics Inc., Regenexbio Inc. and CereSpir Inc. TMW is an academic editor for Scientific Reports. EDAT- 2020/09/18 06:00 MHDA- 2020/12/22 06:00 PMCR- 2020/09/16 CRDT- 2020/09/17 05:40 PHST- 2020/01/15 00:00 [received] PHST- 2020/08/26 00:00 [accepted] PHST- 2020/09/17 05:40 [entrez] PHST- 2020/09/18 06:00 [pubmed] PHST- 2020/12/22 06:00 [medline] PHST- 2020/09/16 00:00 [pmc-release] AID - 10.1038/s41598-020-72075-7 [pii] AID - 72075 [pii] AID - 10.1038/s41598-020-72075-7 [doi] PST - epublish SO - Sci Rep. 2020 Sep 16;10(1):15157. doi: 10.1038/s41598-020-72075-7.