PMID- 26707855 OWN - NLM STAT- MEDLINE DCOM- 20161228 LR - 20181113 IS - 1559-1174 (Electronic) IS - 1535-1084 (Linking) VI - 18 IP - 1 DP - 2016 Mar TI - Proteomic Profiling in the Brain of CLN1 Disease Model Reveals Affected Functional Modules. PG - 109-33 LID - 10.1007/s12017-015-8382-6 [doi] AB - Neuronal ceroid lipofuscinoses (NCL) are the most commonly inherited progressive encephalopathies of childhood. Pathologically, they are characterized by endolysosomal storage with different ultrastructural features and biochemical compositions. The molecular mechanisms causing progressive neurodegeneration and common molecular pathways linking expression of different NCL genes are largely unknown. We analyzed proteome alterations in the brains of a mouse model of human infantile CLN1 disease-palmitoyl-protein thioesterase 1 (Ppt1) gene knockout and its wild-type age-matched counterpart at different stages: pre-symptomatic, symptomatic and advanced. For this purpose, we utilized a combination of laser capture microdissection-based quantitative liquid chromatography tandem mass spectrometry (MS) and matrix-assisted laser desorption/ionization time-of-flight MS imaging to quantify/visualize the changes in protein expression in disease-affected brain thalamus and cerebral cortex tissue slices, respectively. Proteomic profiling of the pre-symptomatic stage thalamus revealed alterations mostly in metabolic processes and inhibition of various neuronal functions, i.e., neuritogenesis. Down-regulation in dynamics associated with growth of plasma projections and cellular protrusions was further corroborated by findings from RNA sequencing of CLN1 patients' fibroblasts. Changes detected at the symptomatic stage included: mitochondrial functions, synaptic vesicle transport, myelin proteome and signaling cascades, such as RhoA signaling. Considerable dysregulation of processes related to mitochondrial cell death, RhoA/Huntington's disease signaling and myelin sheath breakdown were observed at the advanced stage of the disease. The identified changes in protein levels were further substantiated by bioinformatics and network approaches, immunohistochemistry on brain tissues and literature knowledge, thus identifying various functional modules affected in the CLN1 childhood encephalopathy. FAU - Tikka, Saara AU - Tikka S AD - Medicum, Biochemistry/Developmental Biology, Meilahti Clinical Proteomics Core Facility, University of Helsinki, P.O. Box 63 (Haartmaninkatu 8), Room C214a, 00014, Helsinki, Finland. AD - Folkhalsan Institute of Genetics, 00014, Helsinki, Finland. FAU - Monogioudi, Evanthia AU - Monogioudi E AD - Folkhalsan Institute of Genetics, 00014, Helsinki, Finland. AD - Joint Research Centre, Directorate D-Institute for Reference Materials and Measurements, Standards for Innovation and Sustainable Development, Geel, Belgium. FAU - Gotsopoulos, Athanasios AU - Gotsopoulos A AD - Brain and Mind Laboratory, Department of Biomedical Engineering and Computational Science (BECS), Aalto University School of Science, 02150, Espoo, Finland. FAU - Soliymani, Rabah AU - Soliymani R AD - Medicum, Biochemistry/Developmental Biology, Meilahti Clinical Proteomics Core Facility, University of Helsinki, P.O. Box 63 (Haartmaninkatu 8), Room C214a, 00014, Helsinki, Finland. FAU - Pezzini, Francesco AU - Pezzini F AD - Department of Neurological and Movement Sciences, University of Verona, 37134, Verona, Italy. FAU - Scifo, Enzo AU - Scifo E AD - Medicum, Biochemistry/Developmental Biology, Meilahti Clinical Proteomics Core Facility, University of Helsinki, P.O. Box 63 (Haartmaninkatu 8), Room C214a, 00014, Helsinki, Finland. AD - Doctoral Program Brain & Mind, University of Helsinki, Helsinki, Finland. AD - Campbell Family Mental Health Research Institute, CAMH, University of Toronto, Toronto, Canada. FAU - Uusi-Rauva, Kristiina AU - Uusi-Rauva K AD - Folkhalsan Institute of Genetics, 00014, Helsinki, Finland. AD - Genomics and Biomarkers, National Institute for Health and Welfare (THL), P.O. Box 30, 00271, Helsinki, Finland. FAU - Tyynela, Jaana AU - Tyynela J AD - Medicum, Biochemistry/Developmental Biology, Meilahti Clinical Proteomics Core Facility, University of Helsinki, P.O. Box 63 (Haartmaninkatu 8), Room C214a, 00014, Helsinki, Finland. FAU - Baumann, Marc AU - Baumann M AD - Medicum, Biochemistry/Developmental Biology, Meilahti Clinical Proteomics Core Facility, University of Helsinki, P.O. Box 63 (Haartmaninkatu 8), Room C214a, 00014, Helsinki, Finland. FAU - Jalanko, Anu AU - Jalanko A AD - Institute for Molecular Medicine (FIMM), University of Helsinki, 00014, Helsinki, Finland. AD - Genomics and Biomarkers, National Institute for Health and Welfare (THL), P.O. Box 30, 00271, Helsinki, Finland. FAU - Simonati, Alessandro AU - Simonati A AD - Department of Neurological and Movement Sciences, University of Verona, 37134, Verona, Italy. FAU - Lalowski, Maciej AU - Lalowski M AUID- ORCID: 0000-0002-3683-4096 AD - Medicum, Biochemistry/Developmental Biology, Meilahti Clinical Proteomics Core Facility, University of Helsinki, P.O. Box 63 (Haartmaninkatu 8), Room C214a, 00014, Helsinki, Finland. maciej.lalowski@helsinki.fi. AD - Folkhalsan Institute of Genetics, 00014, Helsinki, Finland. maciej.lalowski@helsinki.fi. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20151226 PL - United States TA - Neuromolecular Med JT - Neuromolecular medicine JID - 101135365 RN - 0 (Nerve Tissue Proteins) RN - EC 3.1.2.- (Thiolester Hydrolases) RN - EC 3.1.2.22 (palmitoyl-protein thioesterase) SB - IM MH - Animals MH - Cells, Cultured MH - Cerebral Cortex/*metabolism/pathology/physiopathology MH - Disease Models, Animal MH - Disease Progression MH - Fibroblasts/metabolism MH - Gene Expression Profiling MH - Humans MH - Laser Capture Microdissection MH - Male MH - Mice MH - Mitochondria MH - Models, Neurological MH - Myelin Sheath/pathology MH - Nerve Tissue Proteins/*biosynthesis/genetics MH - Neurites/pathology MH - Neuronal Ceroid-Lipofuscinoses/genetics/*metabolism/pathology/physiopathology MH - *Proteomics MH - Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization MH - Thalamus/*metabolism/pathology/physiopathology MH - Thiolester Hydrolases/deficiency/genetics OTO - NOTNLM OT - Classic infantile NCL OT - LC-MSE, lysosomal storage disorders OT - Laser capture microdissection OT - MALDI-MSI OT - PPT1-palmitoyl-protein thioesterase 1 OT - RNA sequence analysis EDAT- 2015/12/29 06:00 MHDA- 2016/12/29 06:00 CRDT- 2015/12/29 06:00 PHST- 2015/08/03 00:00 [received] PHST- 2015/12/15 00:00 [accepted] PHST- 2015/12/29 06:00 [entrez] PHST- 2015/12/29 06:00 [pubmed] PHST- 2016/12/29 06:00 [medline] AID - 10.1007/s12017-015-8382-6 [pii] AID - 10.1007/s12017-015-8382-6 [doi] PST - ppublish SO - Neuromolecular Med. 2016 Mar;18(1):109-33. doi: 10.1007/s12017-015-8382-6. Epub 2015 Dec 26.