title: Gene dysregulation is restored in the Parkinson's disease MPTP neurotoxic mice model upon treatment of the therapeutic drug Cu(II)(atsm).
abstract: The administration of MPTP selectively targets the dopaminergic system resulting in Parkinsonism-like symptoms and is commonly used as a mice model of Parkinson's disease. We previously demonstrated that the neuroprotective compound Cu(II)(atsm) rescues nigral cell loss and improves dopamine metabolism in the MPTP model. The mechanism of action of Cu(II)(atsm) needs to be further defined to understand how the compound promotes neuronal survival. Whole genome transcriptomic profiling has become a popular method to examine the relationship between gene expression and function. Substantia nigra samples from MPTP-lesioned mice were evaluated using whole transcriptome sequencing to investigate the genes altered upon Cu(II)(atsm) treatment. We identified 143 genes affected by MPTP lesioning that are associated with biological processes related to brain and cognitive development, dopamine synthesis and perturbed synaptic neurotransmission. Upon Cu(II)(atsm) treatment, the expression of 40 genes involved in promoting dopamine synthesis, calcium signaling and synaptic plasticity were restored which were validated by qRT-PCR. The study provides the first detailed whole transcriptomic analysis of pathways involved in MPTP-induced Parkinsonism. In addition, we identify key therapeutic pathways targeted by a potentially new class of neuroprotective agents which may provide therapeutic benefits for other neurodegenerative disorders.
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Melbourne, Melbourne, Victoria, 3010, Australia.|Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Victoria, 3010, Australia.|Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Victoria 3086, Australia.
authors.forename: Lesley
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Melbourne, Melbourne, Victoria, 3010, Australia.|Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Victoria, 3010, Australia.
authors.forename: Camelia Y J
authors.initials: CY
authors.lastname: Quek
authors.affiliation: Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Victoria, 3010, Australia.|The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Victoria 3010, Australia.
authors.forename: Lin W
authors.initials: LW
authors.lastname: Hung
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Melbourne, Melbourne, Victoria, 3010, Australia.|Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Victoria, 3010, Australia.
authors.forename: Robyn A
authors.initials: RA
authors.lastname: Sharples
authors.affiliation: Department of Pharmacology and Therapeutics, The University of Melbourne, Melbourne, Victoria, 3010, Australia.|Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Victoria, 3010, Australia.
authors.forename: Nicki A
authors.initials: NA
authors.lastname: Sherratt
authors.affiliation: Department of Pharmacology and Therapeutics, The University of Melbourne, Melbourne, Victoria, 3010, Australia.|Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Victoria, 3010, Australia.|The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Victoria 3010, Australia.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Barnham
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Melbourne, Melbourne, Victoria, 3010, Australia.|Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Victoria, 3010, Australia.|Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Victoria 3086, Australia.
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Hill
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000009:adverse effects; D000818:Animals; D020013:Calcium Signaling / Q000235:genetics; D056831:Coordination Complexes; D004195:Disease Models, Animal; D004298:Dopamine / Q000096:biosynthesis* / Q000235:genetics; D059290:Dopaminergic Neurons / Q000378:metabolism; D020267:MPTP Poisoning / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D009942:Organometallic Compounds / Q000627:therapeutic use*; D010300:Parkinson Disease / Q000235:genetics* / Q000473:pathology; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000235:genetics*; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism*; D009435:Synaptic Transmission / Q000235:genetics*; D013882:Thiosemicarbazones / Q000627:therapeutic use*
chemical_list: D056831:Coordination Complexes; D018696:Neuroprotective Agents; D009942:Organometallic Compounds; D013882:Thiosemicarbazones; C089548:copper (II) diacetyl-di(N(4)-methylthiosemicarbazone); D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D004298:Dopamine