title: Decreased sensitivity of palmitoyl protein thioesterase 1-deficient neurons to chemical anoxia.
abstract: Infantile CLN1 disease, also known as infantile neuronal ceroid lipofuscinosis, is a fatal childhood neurodegenerative disorder caused by mutations in the CLN1 gene. CLN1 encodes a soluble lysosomal enzyme, palmitoyl protein thioesterase 1 (PPT1), and it is still unclear why neurons are selectively vulnerable to the loss of PPT1 enzyme activity in infantile CLN1 disease. To examine the effects of PPT1 deficiency on several well-defined neuronal signaling and cell death pathways, different toxic insults were applied in cerebellar granule neuron cultures prepared from wild type (WT) and palmitoyl protein thioesterase 1-deficient (Ppt1-/-) mice, a model of infantile CLN1 disease. Glutamate uptake inhibition by t-PDC (L-trans-pyrrolidine-2,4-dicarboxylic acid) or Zn2+-induced general mitochondrial dysfunction caused similar toxicity in WT and Ppt1-/-cultures. Ppt1-/-neurons, however, were more sensitive to mitochondrial complex I inhibition by MPP+(1-methyl-4-phenylpyridinium), and had significantly decreased sensitivity to chemical anoxia induced by the mitochondrial complex IV inhibitor, sodium azide. Our results indicate that PPT1 deficiency causes alterations in the mitochondrial respiratory chain.
authors.affiliation: Sanford Children's Health Research Center, Sanford Research, 2301 E. 60th Street, Sioux Falls, SD, 57104, USA.
authors.forename: Meredith
authors.initials: M
authors.lastname: Meyer
authors.affiliation: Sanford Children's Health Research Center, Sanford Research, 2301 E. 60th Street, Sioux Falls, SD, 57104, USA.|Department of Pediatrics, Sanford School of Medicine, University of South Dakota Sioux Falls, Sioux Falls, SD, 57104, USA.
authors.forename: Attila D
authors.initials: AD
authors.lastname: Kovács
authors.affiliation: Sanford Children's Health Research Center, Sanford Research, 2301 E. 60th Street, Sioux Falls, SD, 57104, USA. PearceD@SanfordHealth.org.|Department of Pediatrics, Sanford School of Medicine, University of South Dakota Sioux Falls, Sioux Falls, SD, 57104, USA. PearceD@SanfordHealth.org.
authors.forename: David A
authors.initials: DA
authors.lastname: Pearce
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology; D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D013869:Thiolester Hydrolases / Q000235:genetics / Q000378:metabolism*
chemical_list: D013869:Thiolester Hydrolases; C095299:palmitoyl-protein thioesterase; D015655:1-Methyl-4-phenylpyridinium
keywords: Batten disease; Cerebellar granule neurons; Cytochrome c oxidase; Infantile CLN1 disease; Palmitoyl protein thioesterase 1; Ppt1 −/−