title: Alterations in striatal dopamine catabolism precede loss of substantia nigra neurons in a mouse model of juvenile neuronal ceroid lipofuscinosis.
abstract: Batten disease, or juvenile neuronal ceroid lipofuscinosis (JNCL), results from mutations in the CLN3 gene. This disorder presents clinically around the age of 5 years with visual deficits progressing to include seizures, cognitive impairment, motor deterioration, hallucinations, and premature death by the third to fourth decade of life. The motor deficits include coordination and gait abnormalities, myoclonic jerks, inability to initiate movements, and spasticity. Previous work from our laboratory has identified an early reduction in catechol-O-methyltransferase (COMT), an enzyme responsible for the efficient degradation of dopamine. Alterations in the kinetics of dopamine metabolism could cause the accumulation of undegraded or unsequestered dopamine leading to the formation of toxic dopamine intermediates. We report an imbalance in the catabolism of dopamine in 3 month Cln3(-/-) mice persisting through 9 months of age that may be causal to oxidative damage within the striatum at 9 months of age. Combined with the previously reported inflammatory changes and loss of post-synaptic D1alpha receptors, this could facilitate cell loss in striatal projection regions and underlie a general locomotion deficit that becomes apparent at 12 months of age in Cln3(-/-) mice. This study provides evidence for early changes in the kinetics of COMT in the Cln3(-/-) mouse striatum, affecting the turnover of dopamine, likely leading to neuron loss and motor deficits. These data provide novel insights into the basis of motor deficits in JNCL and how alterations in dopamine catabolism may result in oxidative damage and localized neuronal loss in this disorder.
authors.affiliation: Center for Aging and Developmental Biology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
authors.forename: Jill M
authors.initials: JM
authors.lastname: Weimer
authors.forename: Jared W
authors.initials: JW
authors.lastname: Benedict
authors.forename: Yasser M
authors.initials: YM
authors.lastname: Elshatory
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Short
authors.forename: Denia
authors.initials: D
authors.lastname: Ramirez-Montealegre
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Ryan
authors.forename: Noreen A
authors.initials: NA
authors.lastname: Alexander
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Federoff
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Cooper
authors.forename: David A
authors.initials: DA
authors.lastname: Pearce
mesh_terms: D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D002394:Catechol O-Methyltransferase / Q000378:metabolism; D016923:Cell Death / Q000235:genetics; D003342:Corpus Striatum / Q000378:metabolism*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics; D008562:Membrane Glycoproteins / Q000172:deficiency; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D018832:Molecular Chaperones; D009043:Motor Activity / Q000235:genetics; D009048:Motor Skills / Q000502:physiology; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D009474:Neurons / Q000473:pathology*; D013378:Substantia Nigra / Q000473:pathology*
chemical_list: C102229:CLN3 protein, mouse; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; D002394:Catechol O-Methyltransferase; D004298:Dopamine